AU723123B2 - Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake - Google Patents

Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake Download PDF

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AU723123B2
AU723123B2 AU23266/97A AU2326697A AU723123B2 AU 723123 B2 AU723123 B2 AU 723123B2 AU 23266/97 A AU23266/97 A AU 23266/97A AU 2326697 A AU2326697 A AU 2326697A AU 723123 B2 AU723123 B2 AU 723123B2
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alkyl
heterocycle
group
compound
aryl
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Shyamal C. Banerjee
Horng-Chih Huang
Len F Lee
Jinglin J. Li
Raymond E. Miller
David B. Reitz
Samuel J Tremont
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GD Searle LLC
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655381—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a seven-(or more) membered ring
    • C07F9/65539—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic

Description

NOVEL BENZOTHIEPINES HAVING ACTIVITY AS INHIBITORS OF ILEAL BILE ACID TRANSPORT AND TAUROCHOLATE UPTAKE BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their
S
use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.
Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et 51\ Biophysica Acta, 1210 (1994) 255-287 discusses the WO 97/33882 PCT/US97/04076 2 biochemistry, physiology and known active agents surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenterology, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihn6r, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August pp. 18035-18046, 1993).
In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549- 967; 0 559 064; and 0 563 731, Hoechst SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTILS97/04076 3 Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.
In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds" Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which islimited by an amide.bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89- 370688; U.S. 3,520,891 abstracted in Derwent 50701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 4 The present invention furthers such efforts by providing novel benzothiepines, pharmaceutical compositions, and methods of use therefor.
SUMMARY OF THE INVENTION Accordingly, among its various apects, the present invention provides compounds of formula S R8
R
6
R
5
R
wherein: q is an integer from 1 to 4; n is an integer from 0 to 2;
R
1 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more 9 substituent selected from the group consisting of OR NR R 0 NRROR A, SR 9 PR R 1 RA S(0)R 9 S2R 9 9 9 9 10 SO3R 9 CO2R CN, halogen, oxo, and CONRR 1 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyl SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 optionally have one or more carbons replaced by O, NR +9 10 9 9 N+R R S, SO, S02, S R PR R 1A-, or phenylene, wherein R R 0 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or
R
1 and R 2 taken together with the carbon to which they are attached form cycloalkylidene;
R
3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR NR R 0 SR S(O)R 9 9 S02R and S03R wherein R 9 and R 10 are as defined above; or 3 4 11 1112
R
3 and R 4 together form =NOR, =NNR R 1 2 =NR or =CR11R 1 2 11 12 wherein R and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, 9 9 10 9 9 cycloalkyl, cyanoalkyl, OR NR R 0 SR S(O)R 9 9 9 9 10 S02R S03R C02R CN, halogen, oxo, and CONR R 0 wherein R 9 and R1 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH2, and SH, or
R
11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl,.aryl, 9 cycloalkyl, heterocycle, quaternary heterocycle, OR, 9 9 9 9
SR
9 S(O)R S02R and S03R, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 6 heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13
NR
13 R' SR 1
S(O)R
13 13 13 R 1 3 1 4
R
13
R
14 1 5 13 S02R ,S03R NR OR NRN R ,N02, C02R ,CN, 13 14 1 41 OM, S020M, S02NR R ,C(O)NR 13
R
1 C(O)OM, C0R 13 13 14 13 14 P(O)R R ,P R R R15A- P (OR" 3
)OR"
4
S'R
13
R
1 4 A, and N +R 9 R 1 1 Rl 2
A-,
wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of-O 7R 7 8 7 7 7 7 7 NR SR S(O)R S02R S03R C02R CN, oxo, 7 8 78 9 CONR R N R R R alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary 7 8 heterocycle, quaternary heteroaryl, P(O)R R 7 89 7 8 P R R R A, and P(O) (OR )OR and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, 7 78 +7 7 NR N R R S, SO, S02, S R PR P(O)R7, 78 13 14 i P R R or phenylene, and R R and R 1 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heterocycle, SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 7 quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9
N+R
9 R10A-, S, SO, SO 2 S+R9A, PR P R R P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R
13
R
14 and R 15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary 9 9 10 9 11 12- 9 9 -heteroaryl, OR NR R0 N R9R 1 R2A SR, S(O)R 9 9 9 9 SO2R S03R oxo, CO2R CN, halogen, CONR R10, 9 10 +910 +9 SO2NR R 0 PO(OR16)OR17, P R R SR and C(O)OM, wherein R 16 and R 17 are independently selected from the substituents constituting R 9 and M, and p is 0 or 1; or 14 15 R and R 1 together with the nitrogen atom to which they are attached, form a cyclic ring; 7 8 R and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle, polyether, quaternary heterocycle, quaternary 13 13 14 13 13 13 heteroaryl, OR, NR R 1 4
SR
1 S(0)R S(0)2R 3 SO3R 3 SR R NR OR4, R
N
3
NR
4
R
15 NO2, C2R 1 3 13 14 14 13 13 14 CN, OM, S020M, SO2NR R 1 4
NR
4 C(O)R C(O)NRR 1 4 1 3 18 18 13 18 NR14C(O)R13, C(O)OM, COR 1 OR S(0)nNR 8
NRR
1 8
NR
1 8
R
1 4 N+R 1
R
1 2 A PR R 1
R
1 2 A amino acid, SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 8 peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9
NR
9
R
1 0 +9 1112 9 9 9 9 9 N R R R A SR S(O)R SO2R S03R oxo, C02R 9 CN, halogen, CONR 9
R
0 SO20M, SO2NR R 1 0 PO(OR) OR 7 +R 9R11R2A S'R9R or C(O)OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituent selected from the group consisting of OR NR R 1 0
NR
9
R
11
R
2 A, SR S(O)R 9 9 9 9 9 10 9 S02R SO3R oxo, CO2R 9 CN, halogen, CONR R 0 SO3R, 9 10 16 17 S020M, S02NR R PO(OR )OR7 and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by 0, NR 13
N+R
13 R14A-, S, SO, S02, S+R3A-, 13 13 14
PR
1 P(O)R13, PR R phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR N+R R A-, +9 9 910 9 S, SO, S02, S R PR P R RA-, or P(O)R; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, SUBSmUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT/US97/04076 9 haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen,
O
13 13 14 13 13 13 13 oxo, OR NR R ,SR ,S(O)R ,S02R ,S03R
NR
1
OR
1 NRXR R15, N02, C02R 13 CN, OM, SO2OM, 114 13 14 13 13 14 S02NR 13 R C(O)NR R C(O)OM, COR ,P(O)R R P+R 13R 14RiA-, P(OR1 3 OR4 S*R 1R 14A, and NR R 9 R 11
R
12
A-,
provided that both R 5and R 6 cannot be hydrogen, 5 1 2 3 4 7 8 OH, or SH and when R is OH, R R R R R and R cannot be all hydrogen; provided that when R5 or R 6 is phenyl, only one of R I or R 2 is H; provided that when q 1 and R' is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Preferably, R 5and R 6can independently be selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, 1 131 1313 13 13 oxo, OR 13 N~R R SR 3 S(O)R S02R, S03R
R
13 0R 14 13 14 15 13 NR OR NR NR R N02, C02R ,CN, OM, S020M, 11413 14 13 13 14 S02NR' 3
R
1 C(O)NR R ,C(O)OM, COR R P +R 13R 14R15A-, P(0R 13 )OR S+R"R and N+R 9 R 1 1 R 12Awherein said alkyl,-alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 can optionally have one or more carbons replaced by 0, 7 78 7 7 NR N R R S, SO, S02, S R PR P(O)R7, P +R 7R 8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 7 8 7 7 7 7 7 NR R SR S(O)R ,S02R S03 R C02R CN, oxo,
CN
7 8 7 8 9 CORR NR R R A- alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7R 8, P +R 7R 8A and P(O) More preferably, R 5 or R' has the formula: -Ar-
(RW)
wherein: t is an integer from 0 to Ar is selected from the group consisting' of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoguinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9 9 9 9 9 SR S(O)R S02R and S03R wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, SUBSITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
O
13
R
13
R
14 13 1 arylalkyl, halogen, oxo, OR NR SR~ 3
S(O)R
13 13 13 14 13 14 15 13 S02R ,S03R ,NR OR N R NR R ,N02, C02R ,CN, 13 14 13 14 1 OM, SO2OM, S02NR R C(O)NR R ,C(O)OM, C0R 13 13 14 13 14 13 P(O)R R ,P R R R15A- P(OR' 3 S'R R"A, and N +R 9 R 1 R 1 2
A-,
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7
R
7 8 77 7 7 7 NR SR S(O)R ,S02R S03 R C02R CN, oxo, 7 8 78 9 CONR R N R R R A- alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary 7 8 78heterocycle, quaternary heteroaryl, P(O)R R P R R A and P(Q) (0R 7 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, 7 78 7 7 NR N R R S, SO, S02, S R. PR P(O)R P +R 7R 8A-, or phenylene.
Most preferably, R 5 or R 6 has the formula (II): SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCTIUS97/04076
(II)
(R)t The invention is further directed to a compound selected from among: R 20 W9 -R 2 1 (Formula DI) R 20- R 19- R 21(Formula DII), and 2 I19 2 R 20 R 19- R 21(Formula DIII) R 23 wherein R" is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTI/US97/04076 13 atoms replaced by O, NR7, N+R7R8, S, SO, S02, S+R7R8, PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, 13 13
R
14 13 13 arylalkyl, halogen, oxo, OR 1 3 NR R 4
SR
1 3
S(O)R
1 13 13 1 3 1 4 1 3 14 1 5 13 S02R 1 3 S03R 3
NR
3 R, NR NR4R 5 N02, CO2R, CN, OM, S020M, S02NR R 4 C(O)NR R C(O)OM, COR 1 3
P()R
1 3
R
1 4 p+R13R14R15A-, P(OR")OR", S'R"R"A and
N+R
9
R
1 1
R
1 2
A;
wherein R' 9 further comprises functional linkages by which R 9 is bonded to R R2, or R in the compounds of Formulae DII and DIII, and R 2 in the compounds of 21 2 21 Formula DIII. Each of R R or R 2 and R 2 comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R 2
R
21
R
22 and R" comprises a benzothiepine moiety corresponding to the Formula: (0on 7 1 2
P
6 4 (Formula DIV) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 or: (Formula DIVA) wherein R 2
R
3
R
4
R
5
R
6
R
7
R
8
R
x q, and n are as defined in Formula I as described above, and R 5 5 is either a covalent bond or arylene.
In compounds of Formula DIV, it is particularly preferred that each of R 2 0
R
21 and R 22 in Formulae DII and DIII, and R 23 in Formula DIII, be bonded at its 7or 8-position to In compounds of Formula DIVA, it is particularly preferred that R 5 comprise a phenylene moiety bonded at a m- or p-carbon thereof to R 9 Examples of Formula DI include: SUBSTIUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCT/IJS97/04076
(III)
(RYA)U,
(Ry)t R 4
A
~R
3
A
,R
2
A
R 8A
(IV)
(Rx)q (R xA )r and SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 16 (RyA)-
R
8
R
1
R
2
/R
4A R4 FO R 19 R2A FRA
(V)
d R1A S R8A 3l r R> R7A (R )e (RX)q In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations.
In any of the compounds of the present invention, R' and R 2 can be ethyl/butyl or butyl/butyl.
In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.
Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 17 administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 18 DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference-in their entirety.
Definitions In order to aid the reader in understanding the following detailed description, the following definitions are provided: "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.
"Aryl" means a fully unsaturated mono- or multiring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures: SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 19 Q Z or
I
z Z"
Z'
wherein Z, Z" or is C, S, P, 0, or N, with the proviso that one of Z, Z" or is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z" or only when each is C.
The term "heteroaryl" means a fully unsaturated heterocycle.
In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a heteroaryl in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.
The term "halogen" means a fluoro, chloro, bromo or iodo group.
The term "haloalkyl" means alkyl substituted with one or more halogens.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 The term "cycloalkyl" means a mono- or multiringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds.
The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.
The term "oxo" means a doubly bonded oxygen.
The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "cycloaklylidene" means a mono- or multiringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.
The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.
The term "peptide" means polyamino acid containing up to about 100 amino acid units.
The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 SUBSTITTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 21 amino acid units.
The term "alkylammoniumalkyl" means a NH 2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.
The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
The term "active compound" means a compound of the present invention which inhibits transport of bile acids.
When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.
The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 22 Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.
The compounds of the present invention also include tautomers.
The compounds of the present invention as discussed below include their salts, solvates and prodrugs.
Compound Syntheses The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
Generally, the compounds of the present invention can be prepared by the procedures described below.
For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methansulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 23 reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one VIII when R' and R 2 are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxides XI when R' and R 2 are nonequivalent.
Optically active compounds of the present invention can be prepared by using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 24 Scheme 1 R1 2HCOH l<0 NaOH
H-
H
HO 11 R' R 2
RH
MsCIINEt 3
H
TV
(Ms methanesulfonyl group) SHO0 MSO.>4 CY R5+ 8 (Rx)q
R
V
VI ZnfrC1 3
ONI
H
IV
NEt 3
R
7
VI
R7R8 Vii Vult excess
MCPBA
R'
H
2 IPd-C
.R
XI
Alternatively, keto-aldehyde VI where R' is H can be prepared by reaction of -thiophenol V with a 2substituted acrolein.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076
RH
SH 0 H S 0
H
RS
5 C N E t 0 (Rx)q
R
3
RX
(RX)q Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-l,1-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R 5 on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R 5 on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT/US97/04076 2 MCPBA NaBH 4 0 (Rx)q (Rx)q
VII
xiI Xa or NaOH
PTC/CH
2 C1 2 (Rx)q (RX*)q MCPBA m-chloroperbenzoic acid PTC phase transfer catalyst when R' butyl, R 2 =ethyl, R 5 =phenyl, X=H, q 4 6a Xa 6b Xb 6c Xc 6d =Xd SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 27 The compounds of the present invention where R 5 is OR, NRR' and S(O)nR and R 4 is hydroxy can be prepared by reaction of epoxide IX where R 5 is H with thiol, alcohol, and amine in the presence of a base.
R
7 8
R
7 8 S R' HOR, or HNRR', or S R' S(2 HS(O),R 'Y R (R )q 0 (RX)q R OH IX, where R 5 H R 5 OR, NRR, S(O)nR Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid.
Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd.
Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.
The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J.
Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 OC, and the rearranged product is hydrolyzed SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCT/US97/04076 28 with sodium hydroxide to yield the thiophenol XVIII.
Similarly, Thiophenol V can also be prepared from 2acyiphenol XIX via the intermediate thiocarbamate
XX.
Scheme 2 (Rx)q potassium t-butoxide (Rx)q SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIEJS97/04076 29 Scheme 3 OH
OH
R 5CH 2 C1 a o R toluene rX XV XVI
S
OH 0 LN(CH3) 1. heat SH 2 R 5 ClC(S)N((CH) 3 2 32 2. NaOH- (Xq(Rx)q
RR)
XVI (RX1q XV11I
S
Y-N(CH
3 2 OHO0 0 0 1. heat SHO0 ClC(S)N((CH) 3 )2 5 2. (Rx)q (Rx)q (Rx)q MXX V Scheme 4 shows another route to benzothiepine-1,ldioxides Xc and Xd starting from the thiophenol XVIII.
Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT1UJS97/04076 SH 6MsO R R 2 RRX)6 R
H
XVIII TV R 7 R R R 7 R R1 0 0 S H 2 MCPBA 0 2 S H (Rx)q (RX)q XXI
XIV
potassiu ptassium t-butxidet-butoxide SSS-
I
0,R R rT V +.~JIR X R R R XXIC XXIId
X
Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-4nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields suif onealdehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 31 with di-t-butyldicarbonate gives the N,O-di-(tbutoxycarbonyl)hydroxylamino derivative XXVI.
Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 32 Scheme
CI
1. Li~S
N
2 32 IV
S
NO,
2
UP]
R R 2 2 MC
S
N. xxiii
NO,
ORI
R 3 R 2
IPBA
xxiv Pd/C (BOC),O
R
3 0 2
S
NHOH
potassium t-butoxide X 2. acid workup N(B0C)O(BO
XXVI
0-,
R'
HOHN 0 2
I<R.
,A bii XXVI1c IPd/C-H 2 100 psi deg C 02 S R'
H
2 NO A ,bH xxxmc 'here R 3 i
HOHN
2
&I(
sHPh
O
XXVI9d IPd/C-H 2 50 deg C 02 Ph 0
OH
XXXIId In Scheme 6, reduction of the sulfone-aldehyde XXV SUBSIUT SHEEF (RULE 26) WO 97/33882 PCTI/US97/04076 33 with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 34 Scheme 6
O
R
H
R
2 a^R H,-Pd/C
R
6
CHIOH
NO,
XXIV
potassium t-butoxide,
THF
2 R6
N
H
XXIxC XXIXd Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII.
Hydrolysis of the carboxylate and derivatization of the resulting acid to acid derivatives are well known in the art.
SUBSTIT.UTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT1UJS97/04076 Scheme 7 ,R 8 (Rx )q* Hg(OTfb) 12,, 25 deg C xxx Pd catalyst COR 7
O
100 deg, C 0 S R xx'i (RX)q- ~XXll Abbreviations used in the foregoing description have the following meanings: THF- tetrahydrofuran PTC---phase transfer catalyst Aliquart 33 6---methyltricaprylylamonium chloride MCPBA r-chloroperbenzoic acid Celite--- a brand of diatomaceous earth filtering SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 36 aid DMF---dimethylformamide DME----ethylene glycol dimethyl ether BOC---t-butoxycarbonyl group R' and R 2 can be selected from among substituted and unsubstituted C, to C10 alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C, to alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CHC(=O)C 2 -CH,OCH., and -CHO-(4picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R' and
R
2 are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (Rx) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxycarbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,Ndialkylamino, (N)-alkoxycarbamoyl, aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, -N-alkylamido, -N,Ndialkylamido, (N)-haloalkylamido, (N)-sulfonamido, alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkyl-amino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, SUBSTITUTE SHEET (RULE 26) WO 97133882 PCT/US97/04076 37 hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute Rx are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,Ndimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium, A -NHC(=O)CH, -NHC(=O) CH 3 carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, -N-methylazetidinium -pyrrolidinyl, pyrrolyl, -N-methylpyridinium -N-methylmorpholinium A-, and N-N'-methylpiperazinyl, (N)-bromomethylamido, N-hexylamino, thiophene, -N (CH,),CO,H I, -NCH 3 CH,CO,H, (N)-N'-dimethylpiperazinium butyloxycarbamoyl, (N)-methylsulfonamido, methylpyrrolidinium, and -(OCH.CH 2 where A is a pharmaceutically acceptable anion. The benzo ring is can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate a 5 or 6 carbon monosaccharide), peptide, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, -(OCHCH,)-NR R RisA-', where x is 2 to 10. Exemplary compounds are those set SUBSTITUTE SHEET (RULE 26) WO 97/33882 38 forth below in Table 1.
PCT1US97104076 SUBSTITUTE SHEET (RULE .26) WO 97/33882 PCT[US97/04076 39 Table 1: Alternative Compounds #3 (Family F1O1.xxx.yyy) 0 0 S R R Prefix Cpd# (FF.xx. yyy) F101.001 01 02 03 04 06 07 08 09 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28
R
1
R
2
R
5 (RX)q ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH3 7-SCH3 7-SOCH3 7-SO 2 CH3 7-SCH 2
CH
3 7-NH 2 7-NHOH 7-NHCH3 7-N(CH3)2 7-N 4
(CH
3 3
I-
7-NHC(=O)CH3 7-N(CH2CH3)2 7-NMeCH2C02H 7-N 4 *(Me) 2 CH2CO2H, I- 7-(N)-morpholine 7-(N)-azetidine 7-(N)-N-methylazetidiniux, I- 7-(N)-pyrrolidine 7-(N)-N-xethyl-pyrrolidiniux, I- 7-(N)-N-rethyl-morpholinium, I- 7-(N)-N'-methylpiperazine 7-(N)-N'-dimethylpiperazinium, I- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 Prefix Cpd# R1,R 2
R
5 (Rx)q (FFF.xxx. yyy) 29 ethyl Ph- 7-NH-CBZ ethyl Ph- 7-NHC(O)C 5
H
11 31 ethyl Ph- 7-NHC(O)CH2Br 32 ethyl Ph- 7-NH-C(NH)NH 2 33 ethyl Ph- 7-(2)-thiophene 34 ethyl Ph- 8-methyl ethyl Ph- 8-ethyl 36 ethyl Ph- 8-iso-propyl 37 ethyl Ph- 8-tert-butyl 38 ethyl Ph- 8-OH 39 ethyl Ph- 8-OCR 3 ethyl Ph- 8-O(iso-propyl) 41 ethyl Ph- 8-SCH 3 42 ethyl Ph- 8-SOCH 3 43 ethyl Ph- 8-SO 2
CH
3 44 ethyl Ph- 8-SCH2CH 3 ethyl Ph- 8-NH 2 46 ethyl Ph- 8-NHOH 47 ethyl Ph- 8-NHCH 3 48 ethyl Ph- 8-N(cH 3 2 49 ethyl Ph- 8-N'(CH 3 3 1ethyl Ph- 8-NHC(=O)CH 3 51 ethyl Ph- 8-N(CH 2
CH
3 2 52 ethyl Ph- 8-NMeCH 2
CO
2
H
53 ethyl Ph- 8-N'(Me) 2 CH2C0 2 H, I- 54 ethyl Ph- 8-(N)-morpholine ethyl Ph- 8-(N)-azetidine 56 ethyl Ph- 8-(N)-N-methylazetidiiu,
I-
57 ethyl Ph- 8-(N)-pyrrolidine 58 ethyl Ph- 8 -(N)-N-methyl-pyrrolidiniu,
I-
59 ethyl Ph- 8-(N)-N-methyl-morpholiniu,
I-
ethyl Ph- 8-(N)-N'-methylpiperazine 61 ethyl Ph- B-(N)-N'-dixethylpiperazinium,
I-
62 ethyl Ph- 8-NH-CBZ 63 ethyl Ph- 8-NHC(O)C5H 11 64 ethyl Ph- 8-NHC(O)CH2Br SUBSTITE SHEE[ (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prof ix CPd# R 1
=R
2 RS (RX) q (FFF. 2xx. yyy) ethyl Ph- 8-NH-C (NH)NH2 66 ethyl Ph- 8-(2)-thiophene 67 ethyl Ph- 9-methyl 68 ethyl Ph- 9-ethyl 69 ethyl Ph- 9-iso-propyl ethyl Ph- 9-tert-butyl 71 ethyl Ph- 9-OH 72 ethyl Ph- 9-OCH3 73 ethyl Ph- 74 ethyl Ph- 9-SCH3 ethyl Ph- 9-SOCH 3 76 ethyl Ph- 9-SO2CH3 77 ethyl Ph- 9-SCH2CH 3 78 ethyl Ph- 9-NH 2 79 ethyl Ph- 9-NHOH ethyl Ph- 9-NHCH 3 81 ethyl Ph- 9-N(CH3)2 82 ethyl Ph- 9-N" (CH 3 3
I-
83 ethyl Ph- 9-NHC CH3 84 ethyl Ph- 9-N (CH 2
CH
3 2 ethyl Ph- 9-NMeCH2CO2H 86 ethyl Ph- 9-N+(Me) 2
CH
2 CO2H, I- 87 ethyl Ph- 9- -morpholine 88 ethyl Ph- 9- -azetidine 89 ethyl Ph- 9-(N)-N-niethylazetidinium, Iethyl Ph- 9 -pyrrol idine 91 ethyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 ethyl Ph- 9-(N)-Nmthyl-morholiniu, I- 93 ethyl Ph- 9 -N I-methylpiperazine 93 ethyl Ph- 9- -dime thylpiperaz inium, Iethyl Ph- 9-NH-CBZ 96 ethyl Ph- 97 ethyl Ph- 9 -NHC (0)CH2 Br 98 ethyl Ph- 9 -NH-C (NH) NH2 99 ethyl Ph- 9 -(2-thiophene SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 Prefix Cpd# (FFP.xxx. yyy) 100 101 102 103 Fl1.1002 01 02 03 04 06 07 08 09 11 12 13 14 16
R
1
=R
2 RB R~ ethyl ethyl ethyl ethyl fl-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n- propy 1 n-propyl n- propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-p ropyl n-propyl n-propyl n-propyl n-propyl.
n-propyl.
n-propyl n-propyl n-propyl n-propyl n-propyl.
ri-propyl n-propyl n-propyl n-propyl Ph Ph,- Ph Ph Ph Ph Ph Ph Ph- Ph Ph- Ph Ph Ph Ph Ph- Ph Ph Ph Ph- Ph Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-OCH 3 8-OCH 3 7-SCH 3 8-OCH 3 7-SCH 3 8-SCH 3 6-OCH 3 7-OCH 3 8-OCH 3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 iso-propyl) 7-SCH 3 7-SOCH 3 7-SO2CH3 7-SCH2CH 3 7-NH 2 7-NHOH 7-NHCH 3 7-N (CH 3 )2 7-N+(CH 3 3
I-
7-NHC CH3 7-N (CH2CH3) 2 7-NMeCH 2
CO
2
H
7-N+ (Me) 2 CH2CO2H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidiniun,
I-
7- -pyrrolidine 7- -N-methyl-pyrrolidiniun,
I-
7- -N-niethyl-morpholiniun,
I-
7- -methylpiperazine -dimethylpiperazinium,
I-
7 -NH-CBZ 7-NiC C 5 Hjl 7 -NHC CH2 Br 7-NH-C (NH)NH 2 SUBSiITU SHEET (RULE 260) WO 97/33882 WO 9733882PCTIUS9 7/04076 Pref ix Cpd# Rl- R2 R 5 (Rx) (FFF. mx. yyy) 33 n-propyl Ph- 7-(2)-thiophene 34 n-propyl Ph- 8-methyl n-propyl Ph- 8-ethyl 36 n-propyl Ph- 8-iso-propyl 37 n-propyl Ph- 8-tert-butyl 38 n-propyl Ph- 8-OH 39 n-propyl Ph- 8-OCH 3 n-propyl Ph- 8-O(iso-propyl) 41 n-propyl Ph- 8-SCH3 42 n-propyl Ph- 8-SOCH 3 43 n-propyl Ph- 8-SO2CH 3 44 n-propyl Ph- 8-SCH 2
CH
3 n-propyl Ph- 8-NH 2 46 n-propyl Ph- 8-NHOH 47 n-propyl Ph- 8-NHCH 3 48 n-propyl Ph- 8-N(CH- 3 2 49 n-propyli Ph- 8-N+(CH 3
I-
n-propyl Ph- 8-NHC(=O)CH 3 51 n-propyl Ph- 8-N(CH2CH3)2 52 n-propyl Ph- 8-NMeCH 2 CO2H 53 n-propyl Ph- 8-N+(Me) 2 CH2CO2H, I- 54 n-propyl Ph- 8-(N)-inorpholiie n-propyl Ph- 8-(N)-azetidine 56 n-propyl Ph- 8- -N-nmethylazetidiniun, I- 57 n-propyl Ph- 8-(N)-pyrrolidine 58 n-propyl Ph- 8- -N-methyl-pyrrolidiniun, I- 59 n-propyl Ph- 8- -N-methyl-morpholiniun, In-propyl Ph- 8- -N'-niethylpiperazine 61 n-propyl Ph- 8-(N)-N'-dimethylpiperaziniun, 1- 62 n-propyl Ph- 8-NH-CBZ 63 n-propyl Ph- 8-NHC(O)C 5 Hll 64 n-propyl Ph- 8-NHC(O)CH2Br n-propyl Ph- B-NH-C(NH)NH2 66 n-propyl Ph- 8-(2)-thiophene 67- n-propyl Ph- 9-methyl 68 n-propyl Ph- 9-ethyl SIJBSITUE SHE (RULE 26) WO 97/33882 WO 9733882PCTIJS97/04076 Pref ix Cpd# ltl.R 2 Rs MY-)q (FFF.xxoc. yyy) 69 71 72 73 74 76 77 78 79 81 82 n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n -propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-buty.
Ph Ph Ph Ph Ph Ph- Ph Ph- Ph Ph Ph Ph Ph- Ph Ph- Ph Ph Ph Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph- 9-iso-propyl 9 -tert-butyl 9-OH 9-OCH 3 9-0 (iso-propyl) 9-SCH 3 9-SOCH 3 9-SO 2 CH3 9-SCH2CH 3 9 -NH2 9-NHOH 9 -NHCH 3 9-N(CH- 3 2 87 88 89 91 92 93 93 96 97 98 99 100 101 102 103 01 9-N 4
(CH
3 3
I-
9 -NHC CH 3 9-N(CH 2
CH
3 2 9 -NMeC- 2 C0 2
H
9-N 4 (Me) 2 CH2CO2H, I- 9- -morpholine 9- -azetidine 9- -N-methylazetidinium, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidinium, I- 9- -N-methyl-morpholiium, I- 9- -methylpiperazine 9- -dimethylpiperazinun, I- 9 -NH-CBZ 9-NHC (0)C 5
H
11 9 -NHC CH2 Br 9-NH-C (NH)NH2 9- -thiophene 7-OCH3, 8-OCH3 7-SCH 3 8-OCH 3 7-SCH 3 8-SCH 3 6-OCH3, 7-OCH 3 8-OCH3 7-methyl F101. .003 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Pref ix Cpd# R 1
.R
2
R
5 (RZ) q (FPF.,ocx. yyy) 02 n-butyl Ph- 7-ethyl 03 ri-butyl Ph- 7-iso-propyl 04 n-butyl Ph- 7-tert-butyl n-butyi Ph- 7-OH 06 n-butyl Ph- 7-0CH 3 07 n-butyl Ph- 08 n-butyl Ph- 7-SCH 3 09 n-butyl Ph- 7-SOCH3 n-butyl Ph- 7-SO 2
CH
3 11 n-butyl Ph- 7-SCH 2
CH
3 12 n-butyl Ph- 7-NH 2 13 n-butyl Ph- 7-NHOH 14 n-butyl Ph- 7-NHCH 3 n-butyl Ph- 7-N(CH3)2 16 n-butyl Ph- 7-N-'(CH3)3, I- 17 n-butyl Ph- 7-NHC(=O)CH3 18 n-butyl Ph- 7-N (CH2CH-3) 2 19 n-butyl Ph- 7-NMeCH-2C02H n-butyl Ph- 7-N'(Me) 2
CH
2 CO2H, I- 21 n-butyl Ph- 7- -morpholine 22 n-butyl Ph- 7- -azetidine 23 n-butyl Ph- 7- -N-xethylazetidiniun, I- 24 n-butyl Ph- 7- -pyrrolidine n-butyJ. Ph- 7-(N-N-rnethyl-pyrrolidilium, I- 26 n-butyl Ph- 7-(N)-N-methyl-morpholiniun, I- 27 n-butyl Ph- 7 -N I -methylpiperaz ine 28 n-butyl Ph- 7-(N)-N'-dixnethylpiperazinium, I- 29 n-butyl Ph- 7-NH-CBZ n-butyl Ph- 7-NHC (0)C 5 Hl 1 31 n-butyl Ph- 7 -NHC(0) CH2 Br 32 n-butyl Ph- 7 -NH-C (NH) NH 2 33 n-butyl Ph- 7- -thiophene 34 n-butyl Ph- 8-methyl n-butyl Ph- 8-ethyl 36 n-butyl Ph- 8- iso-propyl 37 ri-butyl Ph- 8-tert-butyl SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 46 Prefix Cpd# R l=R 2
R
5 (Rx)q (FFF.,acx. yyy) 38 n-butyl Ph- 8-OH 39 n-butyl Ph- 8-OCH3 n-butyl Ph- 8-O(iso-propyl) 41 n-butyl Ph- 8-SCH 3 42 n-butyl Ph- 8-SOd-I 3 43 n-butyl Ph- 8-SO2CH 3 44 n-butyl Ph- 8-SCH 2
CH
3 n-butyl Ph- 8-NH2 46 n-buty. Ph- 8-WHON 47 n-butyl Ph- 8-NHCH3 48 n-butyl Ph- 8-N(CH 3 2 49 n-butyl Ph- 8-N"*(CH 3 3 n-butyl Ph- S-NHC(=O)CH 3 51 n-butyl Ph- 8-N(CH 2
CH
3 2 52 n-butyl Ph- 8-NMeCH2CO 2
H
53 n-butyl Ph- 8-N'(Me) 2
CH
2
CO
2 H, I- 54 n-butyl Ph- 8-(N)-morpholine n-buty. Ph- 8-(N-azetidine 56 n-butyl Ph- 8-(N)-N-rnethylazetidinium, I- 57 n-butyl Ph- 8-(N)-pyrrolidine 58 n-butyl Ph- 8-(N-N-methyl-pyrrolidinium,
I-
59 n-butyl Ph- 8-(N)-N-methyl-torpholiniun, In-butyl Ph- 8-(N)-N'-methylpiperazine 61 n-butyl Ph- 8-(N-N'-dimethylpiperaziniun, 1- 62 n-butyl Ph- 8-NH-CBZ 63 n-butyl Ph- 64 n-butyl Ph- 8-NHC(O)CH 2 Br n-butyl Ph- 8-NH-C(NH)NH2 66 n-butyl Ph- 8-(2)-thiophene 67 n-butyl Ph- 9-methyl 68 n-butyl Ph- 9-ethyl 69 n-butyl Ph- 9-iso-propyl n-butyl Ph- 9-tert-butyl 71 ri-butyl Ph- 9-OH 72 n-butyl Ph- 9-OCH3 73 n-butyl Ph- 9-O(iso-propyl) SUBSTITUTE SHEET (RULE 26P WO 97/33882 WO 9733882PCTIUS97/04076 Pref ix Cpd# RlmR 2 R5 (Rc)q (11.mx. yyy) 74 76 77 78 79 81 82 87 88 89 91 92 93 93 96 97 98 99 100 102 103 F101. 004 01 02 03 04 06 n- bu tyl n- butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n- butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-pentyl n-pentyl n-pentyl n-perityl n-pentyl n-pentyl Ph- Ph- Ph Ph- Ph Ph Ph Ph- Ph Ph Ph- Ph Ph Ph- Ph- Ph- Ph Ph- Ph Ph- Ph Ph- Ph 9-SCHi 3 9-SOCH3 9-SO2CH3 9- SCH 2 CN3 9-NH 2 9-NHOH 9-NHCH3 9-N (CH 3 )2 9-N+(CH 3 3
I-
9-NHC CH3 9-N (CH2CH3) 2 9-NI~eCH 2
CO
2
H
9-N+(Me) 2 CH2C 2
I-
9- -morpholine 9- -azetidine 9- (N)-N-methylazetidiniun, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidinium, I- 9- (N)-N-rnethyl-rorpholinium, I- 9- -methylpiperazine 9- (N)-N'-dimethylpiperazinium, I- 9-NH-CfBZ 9-NHC(O) CSHli 9-NHC CH2Br 9-NH-C (NH) NH2 9 -thiophene 7-OCH3, 8-OCH3 7-SCH3. 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8-OCH 3 7-methyl 7-ethyl 7- iso-propyl 7-tert-butyl 7-OH 7-OCH3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 Prefix Cpd# Rl 1 yR 2 R5 (Rr-)q (F*FF. xxx. yyy) 07 08 09 11 12 13 14 16 n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-perntyl n-pefltyl 7-0 (iso-propyl) 7-SCH 3 7-SOCH 3 7-S02CH 3 7- SCH 2
CH
3 7-NH 2 7-NHOHi 7-NHCH 3 7-N (CH3) 2 7-N-'-(CH 3 3 1- 7-NHC
CH
3 7-N (CH2CH3) 2 7 -N~eCH 2
CO
2
H
7-N* (Me) 2 CH2CO 2 H, I- 7- -iorpholine 7- -azetidine 7- -N-methylazetidiniun, I- 7- -pyrrolidine 7- (R')-N-xnethyl-pyrrolidiniun, I- 7- -N-methyl-rnorpholiniun, I- 7-i(N) -iethylpiperazine 7- -dimethylpiperazinium, I 7 -NH-CBZ 7-NHC 7-NHC CH2Br 7-NH-C (NH)NH2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8- SCH3 8-SOCH3 SUBSiTIJI SHEEF (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Pref ix Cpd# Rl=R 2
R
5 (RX)q( (FFF. xxx. yyy) 43 n-pentyl Ph- 8-S0 2
CH
3 44 n-pentyl Ph- 8-SCH 2 CH3 n-pentyl Ph- 8-NH2 46 n-pentyl Ph- 8-NHOH 47 n-pentyl Ph- 8-NHCH 3 48 n-pentyl Ph- 8-N(CH 3 2 49 n-pentyl Ph- 8-N'(CH3)3, In-penty. Ph- 8-NHC(=O)CH 3 51 n-pentyl Ph- 8-N(CH 2
CH
3 2 52 n-pentyl Ph- 8-N~eCH 2
CO
2
H
53 n-pentyl Ph- 8-N'(Me) 2 CH2CO 2 H, I- 54 n-pentyl Ph- 8-(N)-rnorpholine n-pentyl Ph- 8-(N)-azetidine 56 n-penty. Ph- 8-(N)-N-methylazetidinium,
I-
57 n-pentyl Ph- 8-(N)-pyrrolidine 58 n-pentyl Ph- 8-(N)-N-methyl-pyrrolidinium,
I-
59 n-pentyl Ph- 8-(N)-N-methyl-rnorpholinlium,
I-
n-pentyl Ph- 8-(N)-NI-methylpiperazine 61 n-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, I- 62 n-pentyl Ph- 8-NH-CBZ 63 n-pentyl Ph- 64 n-pentyl Ph- 8-NHC(O)CH 2 Br n-pentyl Ph- 8-NH-C(NH)NH 2 66 n-pentyl Ph- 8-(2)-thiophene 67 n-pentyl Ph- 9-methyl 68 n-perityl Ph- 9-ethyl 69 n-pentyl Ph- 9-iso-propyl n-pentyl Ph- 9-tert-butyl 71 n-pentyl Ph- 9-OH 72 n-pentyl Ph- 9-OCH3 73 n-pentyl Ph- 9-O(iso-propyl) 74 n-pentyl Ph- 9-SCH 3 n-pentyl Ph- 9-SOCH 3 76 n-pentyl Ph- 9-SO2CH3 77 n-pentyl Ph- 9-SCH 2
CH
3 78 n-pentyl Ph- 9-NI12 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Pref ix Cpd# R 1
=R
2
R
5 (RX)qc (FFP. ocx. yyy) 79 81 82 83 84 86 87 88 89 91 92 93 93 96 97 98 99 100 101 102 103 F101.005 01 02 03 04 06 07 08 09 11 n-pentyl n -penty 1 n-pentyl fl-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl 9 -NHOH 9 -NHCH 3 9 -N (CH 3 2 9-N+(CH 3 3
I-
9 -NHC CH 3 9-N(CH 2
CH
3 2 9 -NMeCH 2
CO
2
H
9-N+ (Me) 2 CH2CO 2 H, I- 9 -morpholine 9- -azetidine 9- -N-methylazetidiniun, 1- 9 -pyrrol idine 9- -N-methyl-pyrrolidinium, I- 9- -N-methyl-rnorpholinium, I- 9 -N -iethylpiperazine 9- -direthylpiperazinium, I- 9-NH--CBZ 9 -NHC C5Hl1I 9-NHC(0)CH 2 Br 9 -NH -C (NH) NH2 9- -thiophene 7-0C1 3 8-OCH3 7-Sd-i 3 8-OCH3 7-SCH 3 8-SCH 3 6-OCH 3 7-OCH 3 8-OCH3 7-methyl 7-ethyl 7-is o-propy.
7 -tert-butyl 7-OH 7-OCH 3 7 -0 (i s o-propyl) 7-SCH 3 7-SOCH3 7-SO2CH3 7 -SCH 2
CH
3 SUBSTITUTE SH-E7. (RULE WO 97133882 WO 9733882PCT1UJS97/04076 Pref ix Cpd# Rl 1
,R
2 R5 (flx)q (FFF. mx. yyy) 12 n-hexyl Ph- 7-NHl 2 13 n-hexy. Ph- 7-NHQH 14 n-hexyl Ph- 7-NHCH 3 n-hexyl Ph- 7-N(CH 3 2 16 n-hexy. Ph- 7-N+(CH 3 3
I-
17 n-hexyl Ph- 7-NHC(=Q)CH 3 18 n-hexyl Ph- 7-N(CH 2
CH
3 2 19 n-hexyl Ph- 7-N~eCH 2 CO2H n-hexyl Ph- 7-N+(Me) 2 CH2CO2H, 1- 21 n-hexyl Ph- 7-(N)-rnorpholine 22 n-hexyl Ph- 7-(N)-azetidine 23 n-hexyl Ph- 7-(N)-N-inethylazetidinium, I- 24 n-hexyl Ph- 7-(N)-pyrrolidine n-hexyl Ph- 7-(N-N--methyl-pyrrolidinium, I- 26 n-hexyl Ph- 7-(N)-N-methyl-morpholinium, I- 27 n-hexyl Ph- 7-(N)-N'-methylpiperazine 28 n-hexyj1 Ph- 7-(N)-N'-dimethylpiperaziniun, I- 29 n-hexyl Ph- 7-NH-CBZ n-hexyl Ph- 31 n-hexyl Ph- 7-NHC(O)CH2Br 32 n-hexyl- Ph- 7-NH-C(NH)NH2 33 n-hexyl Ph- 7-(2)-thiophene 34 n-hexyl Ph- 8-methyl n-hexyl Ph- 8-ethyl 36 n-hexyl Ph- 8-iso-propyl 37 n-hexyl Ph- 8-tert-butyl 38 n-hexyl Ph- 8-OH 39 n-hexyl Ph- 8-OCH3 n-hexyl Ph- 8-O(iso-propyl) 41 n-hexyl Ph- 8-SCH3 42 n-hexyl Ph- 8-SOCH3 43 n-hexyl Ph- 8-SO2 CHi 44 n-hexyl Ph- 8-SCH2CH3 n-hexyl Ph- 8-NH2 46 n-hexyl Ph- 8-NHOH 47 n-hexyl Ph- 8-NHCH 3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCT/US97/04076 Prefix Cpd# (FFF.ocx. yyy) 48 49 51 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82
R
1
.:R
2 RS (R 5 )q n-hexyl n- hexyl n-hexyl n-hexyl n-hexyl n-hexyl n- hexyl ri-hexyl n-hexyl n-hexy 1 n- hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexy.
n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl Ph- 8-N (0H3) 2 Ph- 8-N+(CH3) 3
I-
Ph- 8-NHC CH 3 Ph- 8-N (CH2CH 3 2 Ph- 8-NI'eCH2CO 2
H
Ph- 8-MN(Me) 2
CH
2
CO
2 H, I- Ph- 8- -morpholine Ph- 8- -azetidine Ph- 8-(N)-N-methylazetidinium, 1- Ph- 8- -pyrrolidine Ph- 8- -N-methyl -pyrrolidiniumI Ph- 8- -N-rnethyl-rorpholinium,
I-
Ph- 8- -NI -methylpiperazine Ph- 8- (N)-N'-dimethylpiperazinium,
I-
Ph- 8-NH-CBZ Ph- 8-NHC (0)C 5
H
1 1 Ph- 8-NHC (0)CH 2 Br Ph- 8-NH-C(NH)NH 2 Ph- 8- -thiophene Ph- 9-methyl Ph- 9-ethyl Ph- 9-isorpropyl Ph- 9-tert-butyl Ph- 9-OH Ph- 9-OCH3 Ph- Ph- 9-SCH 3 Ph- 9-SOCH 3 Ph- 9-SO2CH 3 Ph- 9-SCH2CH 3 Ph- 9-NH 2 Ph- Ph- 9-NHCH 3 Ph- 9-N(CH3)2 Ph- 9-N' (CH 3 3 1- Ph- 9-NHC(=O)CH 3 83 n-hexyl SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prefix Cpd# Rl 1
_R
2 R5 q (PFF. xcx. yyy) 84 86 87 88 89 91 92 93 93 96 97 98 99 100 101 102 103 01 02 03 04 06 07 08 09 11 12 13 14 16 n-hexyl n -hexy 1 n-hexyl n-hexyl n -hexyl n- hexy 1 n-hexyl n-hexyl n -hexy 1 n -hexy 1 n-hexyl n-hexyl n- hexyl n -hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl is o-propyl iso-propyl i so-propyl i so-propyl iso-propyl i so-propyl i so-propyl iso-propyl is o-propyl i so-propyl is o-propyl Ph- Ph Ph- Ph Ph Ph Ph Ph Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- 9-N (CH2CH3 )2 9-NMeCH 2
CO
2
H
9-N' (Me 2 CH2CO 2 H, I- 9-M()-morpholine 9- (N)-azetidine 9-M()-N-znethylazetidinium, I- 9- -pyrrolidine 9- -N-rnethyl-pyrrolidinium,
I-
9- (N)-N-methyl-morpholinium,
I-
9- -methylpiperazine 9- -dimethylpiperazinium, I- 9-NH -CB Z 9-IN~HC 9-NHC(O) CH2Br 9 NE- C (NH) NH 2 9- (2)-thiophene 7-OCH 3 8-OCH 3 7-SCH 3 8-OCH3 7-SCH 3 8-SCH 3 6-OCH 3 7-OCH3, 8-OCH 3 7-methyl 7-ethyl 7-iso-propyl 7- tert -butyl 7-OH 7-OCH3 7-0 (iso-propyl) 7- SCH-4 7-SOCH 3 7-SQ2CH 3 7-SCH2CH 3 7 -NH2 7-NHOH 7-NHCH 3 7-N (CH3)2 7-N+(CH 3 3
I-
006 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prefix Cpd# (PFF.xacx. yyy) 17 18 19 21 22 23 24 26 27 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49
R
1
=.R
2
R
5 MY-)q iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl i so-propy 1 i so-propyl iso-propyl iso -propyl iso- propyl is o-propyl iso-propyl iso-propyl iso -propyl i so-propyl is 0-propyl is o-propyl is 0-propyl iso-propyl is 0-pr opyl i so-propyl iso-propyl i so-propyl iso-propyl i so-propyl i so-propyl i so-propyl i so-propyl i so-propyl iso-propyl Ph- Ph Ph- Ph Ph Ph Ph Ph Ph- Ph Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph Ph Ph- Phph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-NHC (=O)CH 3 7-N (CH 2
CH
3 2 7-N~eCH 2
CO
2
H
7-N'(Me) 2
CH
2
CO
2 H, I- 7- -morpholine 7- -azetidine 7-M()-N-rnethylazetidinjum, i- 7- -pyrrolidine 7- -N-rnethyl-pyrrolidinium,
I-
7- -N-methyl-morpholinium,
I-
7- -methylpiperazine 7- -dimethylpiperazinium,
I-
7-NH -CBZ 7-NHC(O) C 5 Hll '7-NHC CH2 Br 7-NH-C(NH)
NH
2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH 3 8-SOCH3 8-SO 2
CH
3 8-SCH2CH3 8 -NH 2 8-NHOH 8 -NHCH3 8-N(CH3) 2 8-N 4 l (CH3) 3, 1- 8 -NHC (=O)CH 3 8-N (CH2CH3) 2 8 -NMeCH2CO2H SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIJS97/04076 Prefix Cpd#t (FFF.xxx. yyy) 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 83 84 86 87 88
R
1
=R
2 Rt 5 (Rx) iso-propyl iso-propyl iso-propyl iso-propyl iso- propyl i so-propyl is o-propyl iso-propyl iso-propyl iso-propyl is o-propyl iso-propyl is o-propyl iso-propyl is o-propy.
iso-propyl iso-propyl is o-propyl iso-propyl iso- propyl i so-propyl iso-propyl iso-propyl iso- propyl i so-propyl iso-propyl i so-propyl i so-propyl iso-propyl is o-propyl is o-propyl is o-propyl is o-propyl i so-propyl i so-propyl iso-propyl Ph- 8-N+(Me) 2 CH2CO2H, I- Ph- 8- -morpholine Ph- 8- -azetidine Ph- 8-(N)-N-methylazetidiniun,
I-
Ph- 8- -pyrrolidine Ph- 8- -N-rnethyl-pyrrolidinium, I- Ph- 8- -N-methyl-rnorpholinium, I- Ph- 8-M()-N'-methylpiperazine Ph- 8- -dirnethylpiperaziiiun,
I-
Ph- 8-NH-CBZ Ph- 8-NHC(0)C 5 Hll Ph- 8-NHC CH2Br Ph- 8-NH-C(NH)NH 2 Ph- 8- -thiophene Ph- 9-methyl Ph- 9-ethyl Ph- 9-iso-propyl Ph- 9-tert-butyl Ph- 9-OH Ph- 9-OCH3 Ph- 9-0 (iso-propyl) Ph- 9-SCH 3 Ph- 9-SOCH 3 Ph- 9-SO2CH 3 Ph- 9-SCH 2
CH
3 Ph- 9-NH2 Ph- 9-NHOH Ph- 9-NHCH 3 Ph- 9-N(CH3) 2 Ph- 9-N+ (CH 3 3 1- Ph- 9-NHC(=O)CH 3 Ph- 9-N (CH2CH 3 2 Ph- 9-NMeCH 2
CO
2
H
Ph- 9-N 4 (Me) 2 CH2CO2H, I- Ph- 9- -morpholine Ph- 9- -azetidine SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT[US97104076 Prefix Cpd# (FFF.xxx. yyy) 89 91 92 93 93 96 97 98 99 100 101 102 103 F101.007 01 02 03 04 06 07 08 09 11 12 13 14 16 RlnR 2
R
5 WR') q is0-pr opyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl i so-propyl iso-propyl i so-propyl iso-propyl iso-propyl iso-propyl i so-propyl is o-propyl is 0-propyl iso-butyl iso-butyl iso- butyl i so-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl i so-butyl iso-butyl iso-butyl iso- butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl i so-butyl iso-buty).
Ph- 9-(N)-N-rnethylazetidiniun,
I-
Ph- 9 -pyrrol idine Ph- 9-(N)-N-methyl-pyrrolidiniun,
I-
Ph- 9- (N)-N-methy1-morpholinium,
I-
Ph- 9- -N'-inethylpiperazine Ph- 9-(N)-N'-dimethylpiperazinium,
I-
Ph- 9-NH-CBZ Ph- 9-NHC(O)C 5 Hl 1 Ph- 9-NHC(O)CH 2 Br Ph- 9-NH-C (NH) NH 2 Ph- 9- (2)-.thiophene Ph- 7-OCH 3 8-OCH 3 Ph- 7-SCH 3 8-OCH3 Ph- 7-SCH3. 8-SCH3 Ph- 6-OCH3, 7-OCH3, 8-OCH3 Ph- 7-methyl Ph- 7-ethyl Ph- 7-iso-propyl Ph- 7-tert-butyl Ph- 7-OH Ph- 7-OCH3 Ph- Ph- 7-SCH 3 Ph- 7-SOCH3 Ph- 7-SO2CH3 Ph- 7-SCH2CH3 Ph- 7-NH2 Ph- 7 -NHOH Ph- 7-NHCH3 Ph- 7 -N (CH3) 2 Ph- 7-N+(CH3)3,
I-
Ph- 7 -NHC CH 3 Ph- 7 -N (CH 2 CH3) 2 Ph- 7-NMeCH2CO2H Ph- 7-N+(Me) 2 CH2CO2H, I- Ph- 7- -morpholine SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT/US97/04076 Pref ix Cpd# RluR 2 Its MY) q (FFP. xxx. yyy) 22 23 24 26 27 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 i so-butyl iso-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso- butyl iso-butyl iso- butyl iso-butyl i so-butyl iso-butyl iso-butyl iso-butyl i so-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl Ph Ph Ph Ph Ph Ph Ph- Ph Ph Ph Ph- Ph Ph Ph Ph Ph Ph Ph Ph- Ph Ph- Ph Ph Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7- -azetidine 7- -N-rnethylazetidiniun, 1- 7- -pyrrolidine 7- -N-xnethyl-pyrrolidiniun, 1- 7- -N-methyl-morpholinium, I- 7- -methylpiperazine 7- -dimethylpiperaziniun, I- 7-NH-CBZ 7-NHC C 5
H
1 1 7-NHC CH2Br 7-NH-C (NH) NH 2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-t.er t- butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH 3 8-SOCH 3 8-S0 2 CH3 8-SCH2CH3 8-NH 2 8-NHOH 8-NHCH3 8-N (CH3 )2 8 (CH3) 3, 1- 8-NHC CH3 8-N (CH2CH3) 2 8-NMeCH 2
CO
2
H
8-N' (Me) 2
CH
2
CO
2 H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidiniun, I- 8- -pyrrolidine SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prefix Cpd# R 1
=-R
2
R
5 (Rx)q (FFF.2acx. yyy) iso-butyl i -so-butyl is o-butyl iso -butyJ.
is o-butyl is 0-butyl i so-butyl iso-butyl iso-butyl iso- butyl iso-butyl iso-butyl iso-butyl iso- butyl i so-butyl iso-butyl iso-butyl iso-butyl iso-butyl1 iso-butyl i so-butyl iso-butyl iso-butyl iso-butyl is 0-butyl iso-butyl iso-butyl i so-butyl i so-butyl iso-butyl iso-butyl iso-butyl i so-butyl iso-butyl i so-butyl i so-butyl 8- -N-methyl--pyrrolidiniumI 8- -N-methyl-morpholinium,
I-
8 -rnethylpiperazine -dimrethylpiperazinium, i- 8-NH-CBZ 8-NRC C5HI 1 8-NHC (0)CH2Br 8-NH-C (NH) NH 2 8- -thiophene 9-methyl 9-ethyl 9-iso-propy.
9-tert-butyl 9-OH 9-OCH 3 9-SCII 3 9-SOCH3 9-SO 2
CH
3 9 -SCH2CH 3 9-NH 2 9-NHOH 9-NHCH 3 9-N(CH3) 2 9 -N""(CH3 3 1 9-NHC CH3 9-N (CH2CH 3 2 9 -NMeCH2CO2H 9-N+ (Me) 2
CH
2
CQ
2 H, I- 9 -morphol ine 9- -azetidine -N-mnethylazetidiniun,
I-
9- -pyrrolidine 9- -N-methyl-pyrrolidinium,
I-
9- -N-rnethyl-morpholiniun,
I-
-methylpiperazine SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Pre fix Cpd# R 1
=R
2 R5 (RX) (FFF. xxx. yyy) F101.008 93 96 97 98 99 100 101 102 103 01 02 03 04 06 07 08 09 11 12 13 14 16 iso- buty 1 iso -bu tyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl.
iso-butyl iso-butyl iso- bu tyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph- Ph Ph Ph Ph Ph- Ph- Ph Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph Ph Ph- Ph Ph- 9- -dimethylpiperazinium, I- 9 -NH-CBZ 9-N-C (O)C 5
H
1 1 9-N-C CH2Br 9 -NH-C (NH) NH 2 9 thiophene 7-OCH3, 8-OCH3 7 -SCH 3 8-OCH 3 7-SCH 3 8-SCH 3 6-OCH 3 7-OCH 3 8-OCH 3 7-methyl 7 -ethyl 7- iso-propyl 7-tert-butyl 7-OH 7-QCH 3 7 -0 (i so-propyl) 7-SCH3 7- SOCH3 7-S02CH 3 7- SCH2CH3 7 -NH2 7 -NIOH 7 -NHCH 3 7 -N (CH3) 2 7-N#(CH3)3,
I-
7 -NHC CH3 7 -N (CH2CH3) 2 7 -NMeCH 2 CO2H 7-N"*(Me) 2 CH2C02H, I- 7 -niorphol ine 7 -azetidine 7- -N-methylazetidinium, I- 7- -pyrrolidine 7- -N-methyl-pyrrolidiniun, I- 7- -N-methyl-morpholinium, I- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9I~7 PCTIUS97/04076 Prefix Cpd# R 1
=R
2
R
5 (Rx)qz (FFF. acx. yyy) 27 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-perityl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl Ph- Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph Ph Ph Ph- Ph Ph 7- -methylpiperazine 7- -N'-dimethylpiperazinium,
I-
7-NH-CBZ 7-NHC (O)C5H 1 1 7 -NHC CH2 Br 7-NH-C (NH)NH 2 7 -thiophene 8 -methyl 8-ethyl 8- iso-propyl 8- tert-butyl 8- OH 8- OCH3 8 -0 (is o-propyl) 8-SCH3 8-SOCH 3 8-SO 2
CH
3 8- SCH2CH 3 8-NH 2 8- NHOH 8 -NHCH3 8-N(CH 3 2 8-N*(CH 3 3
I-
8 -NBC CH3 8-N (CH 2
CH
3 2 8 -N~eCH 2 00 2
H
8-N+(Me) 2
CH
2 CO2H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidinium, I- 8- -pyrrolidine 8- -N-methyl-pyrrolidinium, I- 8- -N-methyl-morpholinium, I- 8 -N I-methylpiperaz ine 8- (N-N'-dimethylpiperaziniun, 1- 8 -NH-CBZ SUBSTIMIT SHEET (RULE 26CU) WO 97/33882 WO 9733882PCT[US97/04076 Prefix Cpd# Rl 1
=R
2
R
5 (1I'x)q (FFF. xxx. yyy) 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl is o-pentyl iso-penty.
iso-pentyl iso-pentyl iso-pentyl iso-penty.
i so-pentyl iso-pentyl Ph- Ph Ph Ph Ph Ph- Ph Ph Ph Ph Ph Ph Ph- Ph Ph Ph Ph Ph Ph- Ph- 8-NHC (0)C 5 Hll 8-NHC CH2Br 8-NH-C (NH) NH 2 8- -thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9- OCH 3 9-0 (iso-propyl) 9- SCH3 9-SOCH 3 9-SO 2
CH
3 9-SCH2CH3 9-NH 2 9-NHOH 9 -NHCH 3 9-N (CH3) 2 9-N"'(CH 3 3
I-
9-NHC CH3 9-N (CH 2
CH
3 2 9 -NMeCH2CO 2
H
9-NI (Me) 2 CH2CO2H, I- 9- -morpholine 9- -azetidine 9-M()-N-methylazetidinium, I- 9- -pyrrolidine 9- -N-rnethyl-pyrrolidiniu. I- 9-M()-N-methyi-xnorpholinium. I- 9-M()-N'-methylpiperazine 9-M()-N'-direthylpiperazinium, I- 9 -NH-CBZ 9-NHC C 5
H
1 1.
9-NHC (0)CH 2 Br 9-NH-C (NH)NH2 Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- SUBSITIIE SHEET (RULE 26L. WO 97/33882 PTU9147 PCTIUS97/04076 Prefix Cpd# Rl.R 2 Rs (RX)q (FFP. 0cx. yyy) F101 009 99 100 101 102 103 01 02 03 04 06 07 08 09 11 12 13 14 16 iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C(=0)C 2 H5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5 9- -thiophene 7-0CM 3 8-OCH 3 7-SCH 3 8-OCH 3 7-SCM 3 8-SCH 3 6-0CM 3 7-OCH 3 8-OCH 3 7-methyl 7-ethyl 7- iso-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 (iso-propyl) 7-SCM 3 7-SOCH 3 7- so2CH 3 7-SCH 2
CH
3 7-NH 2 7-NHOH 7-NHCH 3 7-N (CH 3 )2 7-N+(CH 3 3
I-
7-NHC
CH
3 7 -N (CH 2
CH
3 2 7-NMeCH2CO2H 7-N+(Me) 2 CH2C02H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidinium, I- 7 -pyrrol idine 7- (N)-N-niethyl-pyrrolidinium, I- 7- (N)-N-methyl-morpholinium, I- 7- -methylpiperazine 7- MN- N' -dime thylp iperaz inium, I- 7-NH-CBZ 7-NHC SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97104076 Prefix Cpd# Rl,=R 2
R~
5 MY~) q (FFPxxx.yyy) 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
HS
CH
2 C (=0)C 2 H5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2 H5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=o)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C2H5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH-
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2 H5
CH
2 C C 2
H
5 Ph Ph Ph- Ph- Ph Ph- Ph- Ph Ph- Ph- Ph Ph Ph- Ph Ph- Ph- Ph Ph- Ph Ph- Ph Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph 7 -NHC CH2Br 7 -NH- C (NHi) NH 2 7 thi ophene 8 -methyl 8- ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH3 8 -SOCH 3 8-SO2CH3 8-SCH2CH3 8-NH2 8-NHOH 8 -NHCH 3 8-N (CH 3 2 8-N+ (CH 3 3, 1- 8-NHC CH3 8-N (CH 2 CH3) 2 8 -NMeCH 2 CO2H 8-N 4 (Me) 2 CH2CO 2 H, I- -morpholine 8-CMN) -azetidine 8- -N-methylazetidinium, I- 8- -pyrrolidine -N-methyl-pyrrolidiniun, I- 8- -N-rethyl-morpholiniun, I- 8- M) -rethylpiperazine -dimethylpiperazinium, I- 8-NH-CBZ 8-NHC C5Hl1 8-NHC CH2Br SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9I47 PCTIUS97/04076 Pref ix Cpd# (FFF.xxx. yyy) 66 67 68 69 71 72 73 74 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 93 96 97 98 Rl.R 2 Rs (RZ) q
CH
2 C C 2
H
5
CI-
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C (=0)C 2
H
5
CI-
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C2H5
CH
2 C C 2 H5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2 H5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
HS
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2
H
5
CH
2 C C 2
HS
8 -NH -C (NH) NH 2 8- -thiophene 9-methyl 9-ethyl 9-is o-propyl 9-tert-butyl 9-OH 9 -OCH3 9 -0 (i iso- propyl) 9-SCH 3 9-SOd-I 3 9-SO2CH3 9 -SCH2CH3 9-NH 2 9-NHOH 9-NHCH 3 9-N(CH 3 2 9-N' (CH3) 3 1- 9-NHC CH 3 9-N(CH2CH3) 2 9-NMeCH2CO2H 9-N 4 (Mie) 2
CH
2 CO2H, I- 9- -morpholine 9 -azetidine 9-(N)-N-xethylazetidiniun, I- 9- -pyrrolidirie 9- (N)-N-methyl-xnorpholiniuni, I- 9- -N -methylpiperazine -dimethylpiperaziniun, I- 9-NH -CBZ 9-NHC 9 -NHC CH2 Br 9-NH-C (NH) NH2 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prefix Cpd# R 1
=R
2
R
5 (Rvx)q (FFF. xxx. yyy) 99 100 101 102 103 Fbil. 010
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C (=0)C 2 11 5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 0C 2
H
5
CH
2 0C 2
H
5
CH
2 0C 2
H
5
CH
2 0C 2
H
5
CH
2 0C2H5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 OC2H 5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2 0C 2
H
5 Ph- Ph Ph- Ph- Ph Ph- Ph- Ph Ph- Ph- Ph Ph- Ph Ph Ph Ph Ph Ph Ph- Ph Ph Ph Ph- Ph Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph Ph Ph- 9- -thiophene 7-OCH 3 8-OCH 3 7-SCH 3 8-OCH 3 7-SCH 3 8-SCH 3 6-OCH 3 7-OCH 3 8-OCH 3 7-methyl ?-ethyl 7-iso-propyl 7-te r t -bu tyl 7-OH 7-OCH 3 7-0 (iso-propyl) 7-SCH 3 7-SOCH3 7-SO2CH 3 7-SCH 2
CH
3 7-NH 2 7 -NHOH 7-NHCH3 7-N (CH3) 2 3 1- 7 -NHC CH3 7-N (CH 2 CH3 2 7 -NMeCH 2 CO2H 7-N" (Me) 2 CH2CO2H, I- 7- -morpholine 7- -azetidirie 7-M()-N-xnethylazetidinium, I- 7- -pyrrolidine 7- -N-methyl-pyrrolidinium, I- 7- -N-methyl-morpholinium, I- 7- -methylpiperazine 7- -dimethylpiperazinium, I- 7-NH-CBZ SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 Prefix Cpd# Rl.R 2
R
5 (RX)q (FFF.xcxx. yyy)
CH
2 0C 2
H
5 Ph- 7-NHC(O)C 5
H
1 1 31 CH 2
OC
2
H
5 Ph- 7-NHC(O)CH 2 Br 32 CH 2
OC
2
H
5 Ph- 7 -NH-C (NH)NH 2 33 CH 2
OC
2 HS Ph- 7 thiophene 34 CH 2
OC
2
H
5 Ph- 8-methyl
CH
2
OC
2
H
5 Ph- 8-ethyl 36 CH 2
OC
2
H
5 Ph- 8-iso-propyl 37 CH 2
C
2
H
5 Ph- 8-tert-butyl 38 CH 2
OC
2
H
5 Ph- 8-OH 39 .CH 2
OC
2
H
5 Ph- 8-OCH 3
CH
2
OC
2
H
5 Ph- 8-O(iso-propyl) 41 CH 2
OC
2
H
5 Ph- 8-SCH3 42 CH 2
OC
2
H
5 Ph- 8-SOCH 3 43 CH 2
OC
2
H
5 Ph- 8-S02CH3 44 CH 2
OC
2
H
5 Ph- 8-SCH2CH 3
CH
2
OC
2
H
5 Ph- 8-NH 2 46 CH 2
OC
2
H
5 Ph- 8-NHOH 47 CH 2
OC
2
H
5 Ph- 8-NHCH 3 48 CH 2
OC
2
H
5 Ph- 8-N(CH3) 2 49 CH 2
OC
2
H
5 Ph- 8-NW(CH 3 3
I-
CH
2
OC
2
H
5 Ph- 8-NHC(=O)CH 3 51 CH 2
OC
2
H
5 Ph- 8-N(CH 2
CH
3 2 52 CH 2
OC
2
H
5 Ph- 8-NMeCH2CO 2
H
53 CH 2
OC
2
H
5 Ph- 8-N'(Me) 2 CH2CO 2 H, I- 54 CH 2
OC
2
H
5 Ph- 8-(N)-morpholine
CH
2
OC
2
H
5 Ph- 8-(N)-azetidine 56 CH 2
OC
2
H
5 Ph- 8-(N)-N-methylazetidinium,
I-
57 CH 2
OC
2
H
5 Ph- 8-(N)-pyrrolidine 58 CH 2
OC
2
H
5 Ph- 8-(N)-N-methyl-pyrrolidinium,
I-
59 CH 2
OC
2
H
5 Ph- 8-(N)-N-methyl-morpholinium,
I-
CH
2 0C 2
H
5 Ph- 8-(N)-N'-methylpiperazine 61 CH 2
OC
2 5 Ph- 8- (N)-N'-dimethylpiperazinium,
I-
62 CH 2
OC
2
H
5 Ph- 8-NH-CBZ 63 CH 2
OC
2
H
5 Ph- SUBSTITUTE SHEET (RULE 26) .WO 97/33982 PCTUS97/04076 Prefix Cpd# (FFF.xxx. yyy) 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 RlR2 R 5 (Rx) q
CH
2
OC
2
H
5
CH
2
C
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2
QC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
HS
CH
2
OC
2
H
5
CH
2
C
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
C
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5 8-NHC(O)CH2Br 8-NH-C (NH)NH 2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH 3 9-SCH 3 9-SOCH 3 9-SO2CH3 9-SCH2CH3 9-NH 2 9-NHOH 9-NHCH 3 9-N(CH 3 )2 9-N+(CH3)3,
I-
9-NHC(=0O)CH 3 9-N(CH 2 CH3)2 9-NMeCH2CO2H 9-N (Me) 2 CH2CO2H, I- 9-(N)-morpholine 9- -azetidine 9-(N)-N-methylazetidinium, I- 9-(N)-pyrrolidine 9-(N)-N-methyl-pyrrolidiniu, I- 9-(N)-N-methyl-morpholinium, I- 9-(N)-N'-methylpiperazine 9-(N)-N'-dimethylpiperazinium, I- 9-NH-CBZ 9-NHC(O)C 5
H
11 9-NHC(O)CH2Br Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 Prefix Cpd# R 1
-R
2
R
5 (Rs (FFF. xxx. yyy) RCq F101. 011 98 99 100 101 102 103 01 02 03 04 06 07 08 09 11 12 13 14 16
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OHi)C 2
H
5
CH
2 CH (OH) C 2
B
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5 Ph Ph- Ph Ph Ph Ph Ph Ph Ph Ph Ph- Ph Ph Ph- Ph- Ph- Ph- Ph Ph- Ph Ph Ph Ph Ph- Ph- Ph- Ph- Ph- Ph Ph Ph- Ph Ph Ph- 9-NH-c (NH)NH 2 9 -thiophene 7-OCH 3 8-OCH 3 7-SCH- 3 8-OCH 3 7-SCH- 3 8-SCH3 6-OCH 3 7-OCH 3 8-OCH 3 7-methyl 7-ethyl 7- iso-propyl 7-r-ert-butyl 7 -OH 7-OCH3 7-0 (is 0-propyl) 7-SCH 3 7-SOCH 3 7-S0 2
CH-
3 7- SCH 2
CH
3 7-NH 2 7-NHOH 7 -NHCH 3 7-N (CH 3 2 7-N"(CH 3 3
I-
7-NHC CH 3 7-N (CH 2
CH
3 2 7 -NMeCH2CO2H 7-N" (Me) 2 CH2CO2H, I- 7- -morpholine 7 (N)-azetidine 7- (N)-N-methylazetidiniun, I- 7- -pyrrolidine 7- (N)-N-methyl-pyrrolidiniun,
I-
7- (N)-N-xnethyl-morpholinium,
I-
7- -methylpiperazine 7- (N-N-dimethylpiperazinium,
I-
SUBSTITUTE SHEET (RULE 26)1 WO 97/33882 PTU9147 PCT/IJS97/04076 Prefix Cpd# (FFP.xxx. yyy) 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49
R
1
=R
2
R
5 (RX)q
CH
2 CH (OH) C 2
H
5
CH
2
CH(OH)C
2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH)C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH)C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5 7-NH-CBZ 7-NHC (0)C 5
H
1 1 7-NHC CH2Br 7-NH-C (NH)NH 2 7 -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8 -OCH 3 8-0( iso-propyl) 8- SCH 3 8 -SOCH3 8-SO2CH 3 8 -SCH 2
CH
3 8-NH 2 8-NHOH 8-NHCH 3 8-N(CH3) 2 8-N 4
(CH
3 3
I-
8-NHC
CH
3 8-N (CH2CH3) 2 8-NMeCH 2
CO
2
H
8-N 4 (Me) 2 CH2CO 2
H,
8- -morpholine 8- -azetidine -N-xnethylazetidinium, I- 8- -pyrrolidine -N-rnethyl-pyrrolidinium, I- -N-methyl-inorpholinium, I- 8- -N -methylpiperazine -dimethylpiperaziniun, I- 8-NH-CBZ SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS9 7/04076 Prefix Cpd# (FFF.xxx. yyy) 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 93 96
R
1
-R
2 Rs (RX) q
CH
2 CH (OH) C 2
H
5 CH2CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH(OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH(OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH(OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5 8-NHC C5H 1 1 -8-NHC (0)CH2Br 8-NH-C (NH) NH 2 8 (2 thi ophene 9-methyl 9-ethyl 9-iso -propyl 9-tert-butyl 9-OH 9 -OCH 3 9-0 (iso-propyl) 9-SC143 9-SOCH 3 9-SO2CH 3 9 -SCH2CH 3 9-NH 2 9-NHOH 9 -NHCH 3 9-N(CH 3 2 9-N+(CH 3 3
I-
9-NHC(=O)CH 3 9-N(CH2CH 3 2 9 -NMeCH2CO 2
H
9-N+ (Me) 2 CH2CO 2
H,
9-(N)-morpholine 9 -azetidine -N-methylazetidinium,
I-
9- -pyrrolidine -N-rnethyl-pyrrolidinium,
I-
-N-methyl-morpholinium,
I-
9- -iethylpiperazine 9- -dirnethylpiperazinium,
I-
9-NH-CBZ 9 -NHC C5HI1 SUBSTIUT SHEET- (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prof ix CPd# Rl=R 2 its (RX) q MrF. xxx.- yyy) 97 98 99 100 101 102 103 F101. 012 01 02 03 04 06 07 08 09 11 12 13 14 16 17 18 19 21 22 23 24 26 27
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline) CH2OT (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 0- (4-picoline) Phph Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph Ph Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-NHC (O)CH2Br 9-NH-C (NH)NH 2 9- -thiophene 7-OCH 3 8-OCH 3 7-SCH3, 8-OCH3 7-SCH 3 8-SCH3 6-OCH3, 7-OCH 3 8-OCH 3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7 -OCH3 7-0 (iso-propyl) 7- SCH 3 7 -SOCH 3 7-SO 2
CH
3 7-SCH2CH 3 7-NH 2 7-NHQH 7 -NHCH3 7-N(CH 3 2 7-N+(CH 3
I-
7-NHC CH3 7 -N (CH2CH3) 2 7 -NMeCH 2 CO2H 7-N' (Me) 2
CH
2
CO
2 H, I- 7- -morpholine 7- -azetidine 7- -N-xnethylazetidinium, I- 7- -pyrrolidine -N-methyl-pyrrolidiniun, I- 7- -N-methyl--morpholinium, I- 7- -methylpiperazine SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9/47 PCTIUS97/04076 Pref ix x.
Cpd# yyy) 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49
R
1
=R
2
R
5 (flX) q
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 Q- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 Q- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 Q- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 Q- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline) Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph-- Ph- 7- -dimethylpiperaziniumI 7-NH-CBZ 7-NHC 7-NHC (O)CH2Br 7 -NH- C (NH) NH 2 7 thiophene 8-methyl 8-ethyl 8- iso-propyl 8-tert-butyl 8-OH 8 -OCH 3 8 -0 (i so-propyl) 8-SCH 3 8-SOCH3 8-S0 2
CH
3 8 -SCH 2
CH
3 8-NH2 8-NHOH 8 -NHCH 3 8-N(CH3) 2 8-N+(CH 3 3
I-
8 -NHC CH3 8-N(CH2CH3) 2 8 -NMeCH2CO2H 8-N+(Me) 2 CH2CO 2 H, I- 8- -morpholine 8 -azetidine 8- -N-methylazetidinium, 1- 8- -pyrrolidine 8- -N-methyl-pyrrolidiniun, I- 8- -N-methyl-morpholiniun,
I-
8- -methylpiperazine 8- -diinethylpiperaziniun, I- SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 Prefix Cpd# RlmR 2
R
5 (Rx)q (FFF. xxx. yyy) 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82
CH
2 O- (4-picoline)
CH
2 0- (4-picoliie)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 0- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH-
2 0- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O0- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picojline)
CH
2 Q- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 0- (4-picoline) Ph Ph Ph- Ph- Ph- Ph- Ph- Ph ph Ph- Ph Ph- Ph Ph Ph- Ph Ph- Ph Ph Ph- Ph Ph Ph Ph Ph- Ph- Ph- Ph Ph- Ph Ph Ph Ph Ph- 8 -NH--CBZ 8-NHC (0)C 5 Hll 8-NHC (0)CH2Br 8-NH-C (NH)NH 2 8- (2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9- OCH 3 9-O(iso-propyl) 9 -SCH 3 9-SOCH 3 9-SO2CH3 9 SCH 2
CH
3 9 -NH2 9- NHOH 9 -NHCH3 9 -N (CH3) 2 9-N+(CH 3 3
I-
9-NHC(=0)CH3 9 -N (CH2CH3) 2 9 -NMeCH2CO2H 9-N 4 (Me) 2 CH2CO2H, I- 9- (N)-rorpholine 9- -azetidine 9- (N)-N-methylazetidinium, I- 9- -pyrrolidine 9- (N)-N-methyl-pyrrolidinium, I- 9- -N-methyl-rnorpholinium, I- 9- -methylpiperazine 9- (N-N-dirnethylpiperazinium, I- 9 -NH-CBZ SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCT/EJS97/04076 Prefix Cpd# R 1 .jR 2
R
5 (Rx)q (FF.,ox.yyy) 96 CH-20-(4-picoline) Ph- 9-NHC (0)C 5
H
1 1 97 CH2O-(4-picoline) Ph- 9-NHC(O)CH 2 Br 98 CH2O-(4-picoline) Ph- 9 -NH-C (NH) NH 2 99 CH 2 O- (4-picoline) Ph- 9- -thiophene 100 CH 2 O-(4-pjcoljne) Ph- 7-OCH 3 8-OCH 3 101 CH2O-(4-picoline) Ph- 7-SCH 3 8-OCH 3 102 CH2O-(4-picoline) Ph- 7-SCH 3 8-SCH 3 103 CH2O-(4-picoline) Ph- 60OCH 3 7>OCH 3 80OCH 3 SUBSTITUTE SHEET (RULE 26) Additional Structures of the Present Invention 00 .110 R 1 (flx)q Compound R I R2 R 3
R
4
R
Nu mberer 101 ethyl n-butyl. OH H phenyl 102 ethyl n-butyl OH H phenyl 103 n-butyl ethyl OH H phenyl 104 ethyl n-butyl OH H phenyl 105 ethyl n-butyl OH H phenyl 106 ethyl n-butyl. OH H phenyl0 107 n-butyl ethyl OH H 4-(decyloxy)phienyl 108 ethyl n-butyl OH H phenyl 109_ ethyl n-butyl OH H 110 ethyl n-butyl OH H phenyl Ill n-butyl ethyl OH H 4;-hydroxyphenyl 112 ethyl n-butyl OH H 0 0
-OH
~113 ethyl n-butyl OH H 4-hydroxyphenyl 11 ethyl n-butyl OH I-I 4-methoxyphenyl 115 n-butyl ethyl OH4 H 4-niethoxyphenyl 1.!16 ethyl n-butyl OH H -4-methoxyphenyl 117 n-butyl ethyl OH H phenyl 118 ethyl n-butyl OH H phenyl 119 ethyl n-butyl OH H phenyl 120 n-butyl ethyl OH H phenyl 0 121 ethyl n-butyl OHl H phenyl 122 n-butyl ethyl OH H phenyl 123 ethyl n-butyl OH1 H phenyl 124 n-butyl ethyl OH H 4fupienyl 125 ebtyl ebtyl OHl H 4fuphenyl 126 ty n-butehyl OH H 4-fluorophenyl 127 ety -uy OH H 4-fluoropheny I 128 ethyl n-butyl OH H 4-fluorophenyl 132 ethyl n-butyl OH H 4fuphenyl 131 ethyl n-butyl OH H 4fophenyl 132 ethyl n-butyl OH H phenyl 133 ethyl n-butyl OH H phenyl 134 ethyl n-butyl OH H phenyl 1357ty n-butetyl OH H pheny] 137 n-butyl ethyl OH H phenyl 138 n-butyl ethyl OH H phenyl 142 ethyl n-butyl H- OH H 143 ethyl n-butyl OH H 3-methoxyphenyl 144 ethyl n-butyl OH H 4-fluorophenyl 262 ethyl n-butyl Off H 3-methoxyphenyl 263 ethyl n-butyl H OH H 264 ethyl n-butyl OH H 3-trifluoromethylphenyl Cd, 1; 265 ehlnbt H OH H 266 ethyl n-butyl OH H -3-hydroxyphenyl 267 ethyl n-butyl OH H 3 -hydroxyphenyl 268 ethyl n-butyl OH H 4-fluorophenyl 269 ethyl: n-butyl H OH H 270 ethyl n-butyl OH H 4-fluorophenyl 271 ethyl n-butyl OH H 3-me thoxyphenyl 272 ethyl n-butyl H OH H 273 ethyl n-butyl H OH H 274 ethyl n-butyl OH H -4-fluorophenyl 275 ethyl n-butyl H OH H 276 ethyl n-butyl OH H -3-methoxyphenyl 277 ethyl n-butyl OH H 3-fl uorophenyl 278 ethyl n-butyl H OH 2-fluorophenyl 279 ethyl n-butyl H OH 3-fluorophenyl 280 ethyl n-butyl OH H -2-fluorophenyl_ 281 ethyl n-butyl OH H 4-fluorophenyl 282 ethyl n-butyl OH H 4-fluorophenyl 283 ethyl n-butyl H OH H 284 ethyl n-butyl OH H 4-fluoropheny I 286 ethyl ethyl OH H phenyl 287 ethyl ethyl OH H phentyl 288 methyl methyl OH H phenyl 289 n-butyl. n-butyl OH H phenyl 290 n-butyl n-butyl OH H phenyl 291 n-butyl n-butyl OH H phenyl 0 00
O.-
292 n-butyl n-butyl OHi H 4- fluorophenyl 293 n-butyl n-butyl OH H phenyl 294 n-butyl n-butyl OH H phenyl 295 ethyl n-butyl OH H 0 296 ethyl n-butyl OH H I
N(CH
3 3 0 1000 ethyl n-butyl OH H N S0 3
H
WO 97/33882 PTU9I47 PCTIUS97/04076 q U
CMJ
Oz o 0J0 71 71 SUBSTITUTE SHEET (RULE 26) 1004 ethyl nbtl OH H
D
00
CF
3 COO- 0
(CH
3
CH
2 3 N Nz 1005 n-butyl n-butyl OH H C3
CF
3 COO- 0cn(CH 3
CH
2 3 N Nz rri _H: 1006 n-butyI n-butyl OH H/
N
m F Br-- -4 -4 00 00
C
0 1012 n-bt n-butyl OH H 4-hydroxyphenyl 0 1013 n-butyl n-butyl OH H
F
l 1014 n-butyl n-butyl OH H 4-methoxyphenyl ca 1015 n-butyl n-butyl OH H F Br- C= 1016 n-butyl n-butyl OH H4 N >~C0 2
H
WO 97/33882 PCT/US97/04076
I
0 00 0 0 0 0 03 SUBSTITUTE SHEET (RULE 26) 0 '0 -a
C~J
Ca
CO
U-I
'0 1
C
C
-i 0% WO 97/33882 WO 9733882PCTIIUS97/04076 0 C SUBSTITUTE SHEEET (RULE 26) WO 97133882 WO 9733882PCT[US97/04076 SUBSTITUTE SHEET (RULE 26) 1027o n-DutyI n-buyl OH H i +1 m N c cn 00 1027 n-butyl n-butyl OH H0
CF)
m
N-.
0 N
+I
1029 n-butyl n-butyl OH. H 03(J cc0
NN
m 00 r- 1030 n-butyl n-butyl OH H3
C'CF
/C 0 0 N(CH 2
CH
3 3 0 '0 tj~ 00
C
WO 97/33882 91 -z SUBSTffEUIE SHEET (ftULE 26)
=&U
PCTIUS97/04076 0 00 00
CD
aI n-butyl
CF
3
CO
2
N(CH
2
CH
3 3 n-butyl 00 1042 n-butyl n-butyl, OH H cI- 0 C=1044 n-butyl n-butyl OH HF m
NFCO
1044 n-butyl n-butyl OH H Fm
CF
3
CO
2 0
N(CH
2
CH
3 3 WO 97/33882 WO 9733882PCTIUS97/04076 SUBSTITUTIE SHEET (RULE 26) I0 0 00 00 tkJ 0 WO 97/33882 PCT/US97/04076
'I.
z z 0 0\/ .0 0 I I o 0 0 SUBSTITUTE SHEET (RULE 26) 1058 n-butyl n-butyl OH H 0
~VN
1059 n-butyl n-butyl OH H FBr 01-
N
1060 ethyl n-butyl OH H 3-tluoro-4-met oxypeny 1061 n-butyl n-butyl OHi H 0 3 0 '0 -a 00 00 t.D '0 -4
C
C
-4 0~ WO 97/33882 100 PCT1US97/04076 0 0 0 o 0 0 SUBSTITUTE SHEET (RULE 26) 0 00 1064 n-butyl n-butyl OH H 00
N
0 m 1065 n-butyl n-butyl OH H Fn 2i
N((CH
2
CH
2
O)
2
CH
3 3 00
C
0j n-butyl
N
WO 97/33882 PCTIUS97/04076 103 /2
C>
SUBSTITUTE SHEET (RULE 26) 1073 n-butyl n-butyl Oil H F Br 1074 ethyl_ n-butyl OH H 3-fluoro-4-methoxyphenyl 1075 n-butyl n-butyl OH H 4-fluorophenyl 1076 n-butyl n-butyl OH H
N(CH
3 3 0 1077 n-butyl n-butyl O1i H 3-hydroxymethylphenyl 1078 ethyl n-butyl OH H 4-hydroxyphenyl WO 97/33882 PCTIIJS97/04076 W O 973388 PC~ US97 0407 Iz 0 SUBSTITUT SHEET (RULE 26) -4 1080 n-butyl n-butyl OH H 000 1081 n-butyl n-butyl OH H
NH
0 0 1082 n-butyl n-butyl OH H 2-pyridyl 1083 n-butyl n-butyl OH H 3 -4 1084 n-butyl n-butyl OH H N+1 3 1085 n-butyl n-butyl OH H thiophen-3-yi 1086 n-butyl n-butyl OH H 03N 1087 n-butyl n-butyl OH- H 1088 ethyl n-uy HH 3,4-methylenedioxyphenyl 0
%D
-4
C
co mr q4
S
tI- 1089 ethyl n-butyl OH H 4-methoxyphenyl 1090 n-butyl n-butyl OH H 3 1091 n-butyl n-butyl OH H 1-+ 0
-J
~IJ
w 00
H
0
U)
'0 -a
A
-a 0~ WO 97133882 WO 9733882PCT/US97/04076 109 SUBSTITUTE SHEET (RULE 26) WO 97/33882 110 PCTIUS97/04076 a o z -d o 0 SUBSTITUTE SHEET (RULE 26) n-butyl n-butyl 0 '0 -a L.a L.a 00 00
H
I-i
H
'0
C
C
-a 0% n-butyl
N(CH
2
CH
3 3 00 1101 n-butyl n-butyl OH H 3-abxmtypey 1102 n-butyl n-butyl OH H3-abxmtypey 1103 n-butyl n-butyl OH H 0 1104 n-butyl n-butyl OH H-ieoy *1105 n-butyl n-butyl OH H -pieroxyhny 0 -4 00 00
H
H
~0 -4
C
-4 0% 1111 n-butyl n-butyf OH H F C3O
(CH
2 )k 0 N >C2 1112 n-butyl n-butyl OH H 4-pyridyl 1113 n-butyl n-butyl OH H IF 0
IN
1114 n-butyl n-butyl OH H 3-methoxyphenyl 111i5 n-butyl n-butyl- OH H 4-fluorophenyl 1116 ethyl n-butyl OH H 3-tolyl 0 '.0
-I
L.J
00 00
H
H
-I
C
C
-1 00
C',
I
I-
m r'3 0) 1127 n-butyl n-butyl OH H 3 1128 n-butyl n-butyl OH H 3-fluoro-4-hydroxyphenyl 1 129 n-butyl n-butyl OH H 4-fluorophenyl 1130 n-butyl n-butyl OH H 3-chloro-4-fluorophenyl 1131 ethl n-buty1 OH H 4-methoxyphenyl 1132 n-butyl n-butyl OH H 1133 n-butyl n-butyl OH H 4-cyanomethylphenyl 1134 ethyl n-butyl OH H 0 1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl w 1136 n-butyl n-butyl OH H
C/N)
c 00 3 1137 n-butyl n-butyl OH H 4-fluorophenyl 1138 n-butyl n-butyl OH H 0 J4 3I' 1139 n-butyl n-butyl OH H 3,4-difluorophenyl 1140 n-butyl n-butyl OH H 3-methoxyphenyl 1141 n-butyl n-butyl OH H 4-fluorophenyl 1142 n-butyl n-butyl OH H F N(H2H 3 2 1143 n-butyl n-butyl H OH H 1144 n-butyl n-butyl OH H 1145 n-butyl n-butyl OH H 4-methoxyphenyl 1146 n-butyl n-butyl OH H f-
(CH
2 1 0 0 N(CH 3 3 1 1 4 7 O HH+mt h x p 1147 n-butyl n-butyl OH H -methoxphenyl 1149 n-butyl n-butyl OH H 4-fluorophenyl 1149 n-butyl n-butyl OH H -methoophenyl 1150 n-butyl ebtyl OH H 3-fur-methoxyphenyl .1151 n-butyl ebtyl OH H 3-lur--exphenyl .1152 n-butyl n-butyl OH H 4fuphenyl -4 1154 n-butyl n-butyl OH H 3-methoxypheny 1155 n-butyl n-butyl OH H 4-fluorophenyl 1156 n-butyl n-butyl OH H 4-fluorophenyl 1157 n-butyl n-butyl OH H 4-fluorophenyl 1158 n-butyl n-butyl OH H 4-pyridinyl, hydrochloride salt 1159 n-butyl ethyl OH H phenyl 1160 n-butyl n-butyl OH H 4-fluorophenyl 1161 n-butyl n-butyl OH H 3,5-dichloro-4-methoxyphenyl 1162 n-butyl n-butyl OH H phenyl 1163 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1164 n-butyl n-butyl OH H 4-pyridinyl 1165 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1166 n-butyl n-butyl OH H 3 -hydroxyphenyl 1 167 n-butyl n-butyl OH H ci INI 0 1168 n-butyl n-butyl OH H 4-hydroxyphenyl 1169 n-butyl n-butyl OH H phenyl 1170 n-butyl n-butyl OH H 3-methoxyphenyl 1171 n-butyl n-butyl OH H 4-(trifluoromethylsulfonyloxy)phenyI 1172 n-butyl n-butyl OH H 4-pyridinyl 1173 n-butyl n-butyl OH H 4-fluorophenyl 1174ethl nbuty OHH 3methxypeny 1174 ethyl n-butyl OH H 3-methoxyphenyl O 1176 n-butyl n-butyl OH H 4-fluorophenyl 1177 n-butyl n-butyl OH H 3-methoxyphenyl 1178 n-buty I butyl OH H 3-(trifluoromethylsulfonyloxy)phenyl 1 179 n-butyl n-butyl OH H phenyl 1180 n-butyl n-butyl OH H phenyl 1181 n-butyl n-butyl OH H 4-fliuorophenyl 1182 n-butyl n-butyl OH H 4-(dimethylamino)phenyl 1183 n-butyl n-butyl OH H 3-methoxyphenyl 1184 n-butyl n-butyl OH H 4-fluorophenyl 1185 n-butyl n-butyl OH H 4-fluorophenyl 1186' n-butyl n-butyl OH H phenyl 1187 n-butyl n-butyl OH H 4-fluorophenyl 1188 n-butyl n-butyl OH H 4-methoxyphenyl 1189 n-butyl n-butyl OH H 3,4-difluorophenyl 1190 n-butyl n-butyl OH H 2-bromophenyl 1191 n-butyl n-butyl OH H 4-(dimethylainino)phenyl 1192 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1193 n-butyl n-butyl OH H 4-(2-(2-methylpropyl))phenyl WO 97/33882 WO 9733882PCTIUS97/04076 122 0 0 0
ON
SUB .0UESET RL 6 1196 n-butyl n-butyl OH H 3 3 1197 n-butyl ethyl R3 R4 R3 R4 phenyl C= 1198 n-butyl n-butyl OHf H 4-(pyridinyl-N-oxide) w cj, m 1199 n-butyl n-butyl OH H 0 00 =n 0 m 3 to .120 /-uy -utlHO 1200 n-butyl n-butyl OH OH
H
U 9 9 9 9 1202 n-butyl n-butyl
N(CHA)
1203 n-butyl n-butyl OH H 1204 n-butyl n-butyl OH H 4-fluorophenyl 1205 n-butyl n-butyl OH H 0 1206 n-butyl n-butyl OH H B I 7' N(0H 2
CH
3 3 1207 n-butyl n-butyl OH H 3 mm-rn C02 1208 n-buty1 n-butyI OH H 4-methoxyphenyl 1209 n-butyl n-butyl acetoxy H phenyl 1210 n-butyl n-butyl OH H 2-(dimethylamino)phenyl 1211 ethyl n-butyl OH H
IK)
k0 3 1212 n-butyl n-butyl OH H 4-methoxyphenyl 1213 n-butyl ethyl H OH H 1214 n-butyl ethyl OH H pheny] 1215 n-butyl n-butyl OH H 4-methoxyphenyl 1216 ethyl n-butyl OH H 0 ~0
-I
~IJ
00 00
H
t~J
CO
C
C/I
m 0) 1217 n-butyl n-butyl OH H 4-carboxyphenyl 1218 n-uy n-uyl OH H 4-methoxyphenyl 1219 n-butyl n-butyl OH H 1220 n-butyl n-butyl OH H 3-methoxyphenyl N(H) 1221 n-butyl n-butyl OH H 0 2
CH
3 1222 n-butyl n-butyl OH H 3-methoxyphenyl 1223 n-butyl n-butyl OH H phenyl 1224 n-butyl n-butyl OH H 3-nitrophenyl 1225 n-butyl ethyl OH H 3-methylphenyl 1226 ethyl n-butyl OH H 1227 n-butyl n-butyl OH H 4-fluorophenyl 1228 n-butyl n-butyl OH H 2-pyrrolyl 1229 n-butyl n-butyl OH H 3-chloro-4-hydroxyphenyl 1230 n-butyl n-butyl OH H phenyl 00 coc S 1232 n-butyl n-butyl H OH 3-thiophenyl 1233 n-butyl n-butyl OH H B m N c 9~ N(CH 3 2 1234 n-butyl n-butyl OH H Br
N(CH
3 3
C
e- Cl, m 1235 n-butyl n-butyl OH H 1236 n-butyl n-butyl OH H 4-(bromomethyl)phenyl 1237 n-butyl n-butyl OH H 1238 n-butyl n-butyl OH H
:F
3 1239 n-butyl n-butyI OH H F NJ Br 1240 n-buty1 n-buty1 OH H 4-methoxy-3-methyIphenyl 1241 n-butyl n-butyl OH H 3-(dimethylaminomethyl)phenyl 1242 n-butyl n-butyl OH H F '0l 1243 n-butyl n-butyl OH H
N(CH
3 3
OH
124n-butyl n-butyl OH H 3-.methoxyphenyl n-butyl n-ty n-butyl n-butyl
OH
n-butyl n-butyl
N(CH
3 2 n-butyl n-uy n-butyl 1252 n-butyl n-butyl OH H
N(CH
2
CH
3 3 1253 n-butyl n-butyl OH H
N(CH
3 cc_ OCH 3 :w 1254 n-butyl n-butyl OH HBr cn mN 1255 n-butyl n-butyl OH H
C=-
1256__ n-butyl +-uy OH(CH 3 3 ophn 1256 n-butyl n-butyl OH H 3-irphenyl 1257 n-butyl n-butyl OH H 4fuphenyl 1259 ethyl n-butyl H OH H 1260 ethyl n-butyl OH H 3-hydroxyphenyl 1261 n-butyl n-butyl OH H 1262' n-butyl n-butyl OH H 2-thiophenyl hi 1263 n-butyl n-butyl OH H 1264 n-butyl n-butyl OH H 4-fluorophenyl 1265 n-butyl n-butyl OH H 4-fluorophenyl ci, :1
C=
r- 00 1266 n-butyl fl-utyl OH H 00
N(CH
3 2 0H 3 1267 n-butyl ethyl OH H 1268 n-butyl n-butyl OH H I
'N(CH
2
CH
3 3 m 0 rn 1269, n-butyl n-butyl OH H 1270 n-butyl n-butyl OH H
F
N Br 0,
C,,
ni !21
I-
Ii, r.3 0) 0 1274 n-butyl n-butyl OH H
C
C
F- 0 m 1276 n-butyl n-butyl OH H2
(CH
2 6
CH(CH
3 2 1 +1N- (CN 6 CH(CFj 3 2 00 3 (CH 2 6
CH(CH
3 2 1277 n-butyl n-butyl OH H F 1278' n-butyl n-butyl OH H I- (CH 2 4
CH
3 +1 N C 2 4
CH
3 (CHt 2 4 CHt 3 1279 n-butyl n-butyl OH H.
I- (0H 2 5 0H 3 +1 H 2 5
CH
3 3 (CHt 2 5 0;H 3 1280 n-butyl n-butyl OH H F 0 N N(CH 3 2 1281 n-butyl n-butyl OH H ~1282 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1283 n-butyl n-butyl OH H 4-hydroxymethylphenyl 1284 n-butyl n-butyl OH H 4-fluorophenyl 1285 n-uy ety OH H phenyl 1286 n-butyl n-butyl OH H F C3O
N((CH
2 3
CH
3 3 1287 n-butyl ethyl OH H 4-hydroxyphenyl 0 1288 n-butyl n-butyl OH H 0 Br 1289 n-butyl n-butyl OH H I- (CH 2 7
CH
3 [0 con 3 (CH 2 7
CH
3 m 1290 n-butyl n-butyl OH H F HO0
N--
CF
3
CO
2 -4 00 1292 n-butyl n-butyl OH H cI- 1293 n-butyl n-butyl OH H
N.-
rn3
(CH
3 3
C\
.N(CH
2
CH
3 2
C,
-N
C=
P;~
IO
1303 n-butyl n-butyl OH H 0 1304 n-butyl n-butyl OH H 3 -methoxyphenyl 1305 n-buty n-butyl OH H 4-fluorophenyl 1306 n-butyl n-butyl OH H 0
O
CF
3 17 n-butyl n-butyl OH H H I I I I I 1308 ethyl n-butyl OH F O 0 0 I'l 1309 n-butyl n-butyl OH H 4-methoxyphenyl 1310 ethyl n-butyl OH H phenyl 1311 n-butyl ethyl OH H phenyl.
1312 n-butyl ethyl OH H phenyl 1313 n-butyl ethyl OH H phenyl.
1314 ethyl n-butyl OH4 H phenyl 1315 ethyl n-butyl OH H phenyl 1316 n-butyl ethyl OH H phenyl 1317 n-butyl ethyl OH H phenyl 1318 ethyl n-butyl OHf H phenyl 1319 ethyl n-butyl OH H 3-methoxyphenyl 1320 ethyl n-butyl OH H phenyl 1321 n-butyl ethyl OH H phenyl 1322 n-butyl n-Dutyl OH H0
N
1323 n-butyl n-butyl OH H0 "N N
N
33r 1325 n-butyl n-butyl OH H 4-((diethyIamino)methy1)phenyI -4 1326 n-butyl n-butyl OH H 0 I- OH N OH 1327 n-butyl n-butyl OH H 3-fluoro-4-hydroxy-5-iodophenyt 1328 n-butyl n-butyl OH H 0 0 610
S
In 3
NN
00 q Y Y Y 1330 n-butyl n-butyl 1331 n-butyl n-butyl OH H F
CF
3
CO
2
N(CH
2
CH
3 3 cj,
C
w
-I
-I
C
-1 rn
C
r.3 0)
U
(n 9-.
F;
I T r Y 1337 n-butyl n-butyl cm
(H
3
C)
3
N
1338 n-butvl n-butvl OH 4' 4 I 4 I 1339 n-butyl n-butyl OH 1340 n-butyl ethyl OH H 1341 n-butyl n-butyl -acetoxy H 3-methoxyphenyl 1342 n-butyl n-butyl OH H 1343 ethyl n-butyl OH H phenyl 134n-butyl n-butyl IOH H 3-fluoro-4-methoxyphenyl
C,,
C',
-1i m Cf, ni ni 134- -ty -uy HHpey 1345 ethyl n-butyl. OH H phenyl 1347 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1348 isobutyl isobutyl OH H phenyl 1349 ethyl n-butyl OH H phenyl 1350 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1351 n-butyl n-butyl OH H
CF
3
CO
2
(CH
3
CH
2
)(C!H
3 2
N
1352 n-butyl n-butyl OH H B r 0 3
CH
2
CH
3
CH
2 3
N
1353 n-butyl n-butyl OH H F00
CF
3
CO
2 <V
N(CH
2
CH
3 3 1354 n-butyl n-butyl OH H F C= N en 0 3 (51 Eli 1355 n-butyl n-butyl OH H Nj +1
NN
T o_ I_ 3 3-
IO
rill
M"
WO 97/33882 W097/3882PCTIUS97/04076 154 cc 0 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTfUS97/04076 155 .0 .0 SUBSTITUTE SHiEE-T (RUL E 26) 1363 n-butyl n-butyl OH H 00 o, 0 0 N N(0H 3 2 co 1364 n-butyl n-butyl OH H lp 1 0 9~ 1365 n-butyl n-butyl OH H 0 N 3I n-butyl n-butyl n-butyl WO 97/33882 WO 9733882PCTIUS97/04 076 158 /z SUBSTITUTE SHEET (RULE 26) 0 I N+ 1372 n-butyl n-butyl OH H
C,,
ca 0 1 '1 NNXN m 3I 1374 n-butyl n-butyl OH H 0 00 I0 /1
N+
0N 3 1375 n-butyl n-butyl OH H ci, -IN 00 1376 n-butyl n-butyl OH H K F/
N+
K0 ai
WO 97/33882 PCT/US97/04076 162 SUBSTITUTE SHEET (RULE 26) m
!ZI
I-
"9 a, 1386 n-butyl n-butyl OH H
N(CH
2
CH
3 3 02 1387 n-butyl n-butyl OH H
F
0+ WO 97/33882 WO 9733882PCTIUS97/04076 165 z 0 00 00
-C
00 C SUB~flJIESHEET (ROLE 26) WO 97/33882 PTU9/47 PCTIUS97/04076 166 7 o 0 *0 -4 SUBSTIWuE SHEET (RULE 26) coI 1393 n-butyl n-butyl OH H
I-+
I
N(CH
2
CH
3 3 1394 n-buyl nbuty OHH 1395 n-butyi n-butyl OH H 1395 n-buyl nbuty OH- 1396 n-butyl n-butyl OH H
J-
~N C H 2
CH
3 3
I
(4 amvY, 1397 n-butyl n-butyl 1398 n-butyl n-butyl OH H N
J
n-butyl n-butyl n-butyl n-butyl
F
N(CH
3 3 c,,
C
C
I-
ni 1405 n-butyl n-butyl OH H 0- c CO 2
H
1406 n-butyl n-butyl OH H m cn 1407 n-butyl n-butyl OH H m rrn (H0 2 3 N -4
ON
VI
Uop El WO 97/33882 PCTIUS97/04076 173 cr) cli +0 LL 0 4dz( .0 SUBSTITUTE SHEET-(RULE 26) WO 97/33882 PCTfUS97/04076 174 z -d -d 00 SUBSrnIrE SEr(RUfLE2)
CD
d: rm Cn pps' cn
RS
3 aq 2n er PrJ P~3 ~Cr) k, WO 97/33882 PTU9/47 PCTIUS97/04076 177 /m o0 SUBSTiTUTE SHEET (RULE 26) WO 97133882 PCT/US97/04076 178 -r 0 04 z__ 0 SIUBSTTUTE SHEET (RULE 26) 0 1424 n-butyl n-butyl OH H 00 N N 1425 n-butyl n-butyl OH H I
C,
C,,
r-
#~N(CH
2
CH
3 3 N N WO 97/33882 PCTIUS97/04076 180 0 00 SUBSTrIUTE SHEET (RULE 26) 1429 n-butyl n-butyl OH H Br +(6H) 1430 n-butyl n-butyl OH H Br
C,,
m+ rn 1431 n-butyl n-butyl OH H CO, _q
N(CH
2
CH
3 3 m 1432 n-butyl n-butyl OH H +1 1433 n-butyl n-butyl OH H
N
N++
0 s 2 HO, _2 0- WO 97/33882 WO 9733882PC171US97/04076 183 SUBSTITUTE SHIEET (RULE 26) Am Im m V3
I
CA
E
9-rn.
CO%
I
I
0 1445 n-butyl n-butyl OH HBr 3 1446 n-butyl n-butyl OH H Br
C
m S3 1447 n-butyl n-butyl OH H F a S03 SOis WO 97/33882 PCT/US97/04076 188 SUBSTITUTE SHEET (RULE 26) w,
C
C,,
rn Compoun d Number R6 (Rx)g 101 H0 0
S
0 0 N N H: 1 HH the 7-position 102 H 7-trimethylammonium iodide 103 H 7-trimethylammonium iodide 104 H 7-dimethylamino 105 H 7-methanesulfonamido 106 H 7-(2'-bromoacetamido) 107 H 7-amino 108 H 7-(hexylamido) 109 H 7-amino 110 H 7-acetamido 111H 7-amino 112 H 7-amino 113 H 7-amino 114 H 7-amino 115 H 7-(O-benzylcarbamato) 116 H 7-(O-benzylcarbamato) 117 H 7-(O-benzylcarbamato) 118 H 7-(O-benzylcarbamato) 119 H 7-(O-tert-butylcarbamato) 120 H 7-(O-benzylcarbamato) 121 H 7-amino 122 H 7-amino 123 H 7-hexylamino 124 H 7-(hexylamino) 125 HI the 8-position 126 H 7-(O-benzylcarbamato) 127 H 7-amino 128 H 7-(O-benzylcarbamato) L- 129 H 7-amino WO 97/33882 PCTIUS97/04076 191 -,0 0 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 192 0 00 7) tn~ SUBSTITUTE SHEFET (RU[E 26) WO 97/33882 WO 9733882PCTf[JS97/04076 193 0 0 0 0* 00 O\ SUBSTITUTE SHEET (RULE 26) the 7-position 141 142 3-methoxy-phenyl 7-methylmercapto 143 H 7-methylmercapto 144 H 7-(N-azetidinyl) 262 H 7-methoxy 263 3-methoxy-phenyl 7-methoxy 264 H 7-methoxy 265 3-trifluoro-methyl- 7-methoxy phenyl 266 H 7-hydroxy 267 H 7-methoxy 268 H 7-methoxy 269 4-fluoro-phenyl 7-methoxy 270 H 7-hydroxy 271 H 7-bromo 272 3-methoxy-phenyl 7-bromo 273 4-fluoro-phenyl 7-fluoro 274 H 7-fluoro 275 3-methoxy-phenyl 7-fluoro 276 H 7-fluoro 277 H .7-methoxy 278 H 7-methoxy 279 H 7-methoxy 280 H 7-methoxy I 281 H 7-methylmercapto 282 H 7-methyl 283 4-fluoro-phenyl 7-methyl 284 H 7-(4'-morpholino) 286 H 7-(O-benzylcarbamato) 287 H 7-amino 288 H 7-amino 289 H 7-amino 290 H 7-amino 291 H 7-(O-benzylcarbamato) 292 H 7-amino 293 H 7-benzylamino 294 H 7-dimethylamnino 295 H 7-amino 296 H 7-amino 1000 H 7-dimethylamino 1001 H 7-dimethylamnino 1002 H 7-dimethylanmino 1003 H 7-dimethylamino 1004 H 7-dimethylarmino 1005 H 7-dimethylamino 1006 H 7-dimethylamino 1007 H 7-dimethylanmino 1008 H 7-dimethylamino 1009 H 7-dimethylamino 1010 H 7-dimethylamino I0 W'i l-#i 1011 H 7-dimethylamino 1012 H 7-dimethylamino; 9-methoxy 1013 H 7-dimethylamino 1014 H 7-dimethylamino; 9-methoxy 1015 H 7-dimethylamino 1016 H 7-dimethylamino 1017 H 7-dimethylarmno ____1018 H 7-dimethylamino 1019 H 7-dimethylamino 1020 H 7-dimethylamino 1021 H 7-dimethylamino 1022 H 7-dimethylamino 1023 H 7-dimethylamino 1024 H 7-dimethylamino 1025 H 7-dimethylamino 1026 H 7-dimethylamino 1027 H 7-dimethylarnino 1028 H 7-dimethylamnino 1029 H 7-dimethylamino 1030 H 7-dimethylamino 1031 H 7-dimethylamino 1032 H 7-dimethyl amiino 1033 H 7-dimethylamino 1034 H 7-dimethylamino 1035 H 7-dimethylamino 1036 H 7-dimethylamino 1037 H 7-dimethylamin o 1038 H 7-dimethylamino 1039 H 7-dimethylamino 1040 H 7-dimethylamino 1041 H 7-dimethyl amino 1042 H 7-dimethylamino 1043 H 7-dimethylamino 1044 H 7-dimethylan-ino 1045 H 7-dimethylarmino 1046 H 7-dimethylaniino 1047 H 7-dimethylamnino 1048 H 7-dimethylamino 1049 H 7-dimethylamino 1050 H 7-dimethylaniino 1051 H 7-dimethylamino 1052 H 7-dimethylarnino 1053 H 7-dimethylamino 1054 H 7-dimethylarnino 1055 H 7-dimethylamino 1056 H 7-dimethylarnino 1057 H 7-dimethylamino 1058 H 7-dimethylamino 1059 H 7-dimethylarmino 1060 H 7-methylamino 1061 H 7-methylamidno 1062' H 7-methylamino
C/)
C/)
m rCO 0) 1063 HI 7-methylamilno 1064 H 7-methylamino 1065 H 7-dimethylamino 1066 H 7-dimethylamino 1067 H 9-dimethylamino 1068 H 7-dimethylamino 1069 H 7-dimethylamino; 1070 H 7-dimethylamino 1071 H 7-dimethylamino 1072 H 7-dimethylamiuno 1073 H 7-dimethylamino 1074 H 7-dimethylamino 1075 H 7-dimethylamino; 9-dimethylaniino 1076 H 7-dimethylanmino 1077 H 7-dimethylamino 1078 H 7-dimethylamino 1079 H 7-dimethylarnino 1080 H 7-dimethylamino 1081 H 7-dimethylamino 1082 H 7-dimethylamino 1083 H 7-dimethylamino 1084 H 7-dimethylarnino 1085 H 7-dimethylarmino 1086 H 7-dimethylamino 1087 H 7-dimethylarnino 1088 H 7-dimethylamino 1089 H 7-dimethylarmino 1090 H 7-dimethylamino 1091 H 7-dimethylamino 1092 H 7-dimethylamino 1093 H 7-dimethylamino 1094 H 7-dimethylamino 1095 H 7-dimethylamino 1096 H 7-dimethylamiuno 1097 H 7-dimethylamino 1098 H 7-dimethylamino 1099 H 7-dimethylamino 1100 H 7-dimethylamino 1101 H 7-dimethylamino 1102 HI 7-dimethylamino 1103 H 7-dimethylamino 1104 H 7-dimethylamino 1105 H 7 -dimethylamino 1106 HI 7-dimethylamino 1107 H 7-dimethylamino 1108 H 7-dimethylamino 1109 H 7-dimethylamino 1110 H 7-dimethylamino 1111 H 7-dimethylamino 1112 H 7-dimethylamino 1113 H 7-dimethylamino 1114 H 7-methylamino 1115 H 7-dimethylamino 1116 H 7-dimethylamino 1117 H 7-dimethylarmino 1118 H 7-dimethylamino 1119 H 7-dimethylamino 1120 H 7-dimethylamino ____1121 H 7-dimethylamino 1122 H 7-dimethylamino 1123 H 7-dimethylarrino 1124 H 7-dimethylamino 1125 H 7-dimethylarmino 1126 H 7-dimethylamino 1127 H 7-dimethylamino 1128 H 7-dimethylamino 1129 H 9-dimethylamino 1130 H 7-dimethylamino 1131 H 7-dimethylamino 1132 H 7-dimethylan-ino 1133 H 7-dimethylainino 1134 H 7-dimethylamino 1135 H 7-dimethylamino 1136 H 7-dimethylamino 1137 H 9-(2',2'-dimethylhydrazino) 1138 H 7-dimethylamino 1139 H 7-dimethylamino 1140 H 7-(2',2'-dimethylhydrazino) 1141 H 7-ethylmethylamino 1142 HI 7-dimethylamino 1143 3-fluoro-4- 7-dimethylamnino methoxy-phenyl 1144 H 7-dimethylanino 1145 H 9-dimethylamino 1146 H 7-dimethylamino 1147 H 7-diethylarnino 1148 H 7-dimethylsulfonium, fluoride salt 1149 H 7-ethylamino 1150 H 7-ethylmethylamino 1151 H 7-dimethylamino 1152 H 7-(ethoxymethyl) methylamino 1153 H 7-methylamino 1154 H 9-methoxy 1155 H 7-methyl 1156 H 7-methylmercapto 1157 H 7-fluoro; 1158 H 7-methoxy 1159 H 7-dimethylan-dno 1160 H 7-diethylamino 1161 H 7-dimethylamino 1162 H 7-dimethylamino 1163 H 7-methoxy 1164 H 7-methoxy 1165 H 7-trimethylammonium iodide 1166 H 7-trimethylanunonium iodide 1167 H 7-dimethylamino 1168 H 7-trimethylammonium iodide 1169 H 8-dimethylamino 1170 H 7-ethylpropylamino 1171 H 7-dimethylamino 1172 H 7-methoxy 1173 H 7-ethylpropylamino 1174 H 7-phenyl 1175 H 7-methylsulfonyl 1176 H 9-fluoro 1177 H 7-butylmethylaxnino 1178 H 7-dimethylamino 1179 H 8-methoxy 1180 H 7-trimethylammonium iodide 1181 H 7-butylmethylainino 1182 H 7-methoxy 1183 H 7-fluoro 1184 H 7-fluoro; 9-fluoro 1185 H 7-fluoro 1186 H 7-fluoro; 9-fluoro 1187 H 7-methyl 1188 H 7-trimethylammonium iodide 1189 H 7-trimethylammonium iodide 1190 H 7-bromo 1191 H 7-hydroxy 1192 H 7-hydroxy 1193 H 7-dimethylarrnno 1194 H 7-dimethylanino 1195 H 7-(4'-methylpiperazin- Il-yl) 1196 H 7-methoxy" 1197 H 7-(N-methyl formamido) 1198 H 7-methoxy 1199 H 7-dimethylamino 1200 phenyl 7-dimethylamino 1201 H 7-methyl 1202 H 7-methoxy 1203 H 7-(4'-tert-butylphenyl) 1204 H 7-methoxy 1205 H 7-dimethylamino 1206 H 7-dimethylamino 1207 H 7-dimethylamino 1208 H 7-dimethylamino 1209 H 7-dimethylphenyl 1210 H 7-dimethylarmino 1211 H 7-dimethylamino 1212 H 9-(4'-morpholino) 1213 3-fluoro-4- 7-dimethylamino methoxy-phenyl 1214 H 7-(N-methylformamido) co
C
C
rm 1215 H 9-methylmercapto 1216 H 7-bromo 1217 H 7-dimethylan-ino 1218 H 9-methylsulfonyl 1219 H 7-dimethylamino 1220 H 7-i sopropylamino 1221 H 7-dimethylanino 1222 H 7-ethylamino 1223 H 8-bromo; 1224 H 7-fluoro 1225 H 7-dimethylamlno 1226 H 7-bromo 1227 H 7-(tert-butylamino 1228 H 8-bromo; 1229 H 7-dimethylamino 1230 H 9-dimethylamino; ___7-fluoro 1231 H 7-dimethylamino 1232 H 9-dimethylamino 1233 H 7-dimethylan-ino 1234 H 7-dimethylarrino 1235 H 7-dimethylamino 1236 H 7-dimethylamino 1237 H 7-dimethylamino 1238 H 7-dimethylanmino 1239 H 7-dimethylaniino 1240 H 7-dimethylaniino 1241 H 7-dimethylamino 1242 H 7-dimethylamino 1243 H 7-dimethylamino 1244 H 1'-methylhydrazido) 1245 H 7-dimethylamino 1246 H 7-dimethylamino 1247 H 7-dimethylamino 1248 H 7-dimethylamino 1249 H 7-dimethy lamino 1250 H 7-dimethylan-dno 1251 H 7-dimethylamino 1252 H 7-dimet~iylamino 1253 H 7-dimethylamino 1254 H 7-dimethylamino 1255 H 7-dimethylamino 1256 H 7-dimethylamino 1257 H 8-bromo; 7-dimethylamino 1258 H 9-(tert-butylamino) 1259 phenyl 7-dimethylamino 1260 H 7-dimethylamino 1261 H 7-dimethylamino 1262 H 7-dimethylamino 1263 H 7-bromo 1264 H 7-isopropylamino 1265 H 9-isopropylanmino 1266 H 7-dimethylamino 1267 H 7-carboxy, methyl ester 1268 H 7-dimethylamino 1269 H 7-dimethylamino 1270 H 7-dimethylarnino 1271 H 7-dimethylamino 1272 H 7-dimetliylarmino 1273 H 7-dimethylamino 1274 H 7-dimethylamino 1275 H 7-dimethylamino 1276 H 7-dimethylamino 1277 H 7-dimethylamino 1278 H 7-dimethylamino 1279 H 7-dimethylamino 1280 H 7-dimethylamino 1281 H 7-dimethylarmino 1282 H 7-trimethylammonium iodide 1283 H 7-dimethylamino 1284 H 9-ethylamino 1285 H 7-dimethylamino 1286 H 7-dimethylarrino 1287 H 7-dimethylamino 1288 H 7-dimethylamino 1289 H 7-dimethylamino I 29 H.-iehlmn ____1290 H 7-dimethylamino 1291 H 7-dimethylamio 1293 H 7-dimethylamno 1293 H 7-dimethylarmino 1294 H 7-dimethylamino 1295 H 7-dimethylainino 1296 H 7-dimethylamino 1____298 H 7-dimethylamino 1299 H 7-dimethylamino 1300 phenyl 7-dimethylan-ino ____1301 H 7-trimethylammonium iodide ____1302 H 9-hydroxy 1303 H 7-dimethylamino 1304 H 7-tert-butylamino 1305 H 9-methylarnino 1306 H 7-dimethylamino 1307 4-methoxy-phenyl 9-(4'-morpholino) ____1308 H 7-dimethylamino 1309 H 9-fluoro 1310 H 7-amino 1311 H 7-(hydroxylamino) 1312 H 8-hexyloxy 1313 H 8-ethoxy 1314 H 7-(hydroxylamino) 1315 H 7-(hexyloxy) 1316 H 8-hydroxy 1317
HI
0
~N(CH
3 3 the 8-position 1318 H 7-dimethylarnino 1319 H 7-fluoro 1320 H 7-amino 1321 H 0 -0 the 8-position 1322 H 7-dimethylamino 1323 H 7-dimethylamino 1324 H 7-dimethylamino 1325 H 7-dimethylamino 1326 H 7-dimethylamino 1327 H 7-dimethylamino 1328 H 7-dimethylamino 1329 H 7-dimethylamino 1330 H 7-d'imethylamino H 7-dimethylamino ____1332 H 7-dimethylarmino ____1333 H 7-dimethylaniino 1334 H 7-dimethylamino 1335 H 7-dimethylamino 1336 H 7-dimethylamino 1337 H 7-dimethylamino 1338 H 7-(4'-methylpiperazinyl) 1339 H 7-dimethylarrino 1340 H 7-methyl 1341 H 7-dimethylarnino 1342 H 7-(4'-fluorophenyl) 1343 H 7-amino 1344 H 7-dimethylarnino 1345 H 7-trimethylanunonium iodide 1346 H 0 the 8-position 1347 H 7-dimethylamino 1348 H 7-dimethylanmino 1349 H 7-dimethylamino 1350 H 7-trimethylammonium iodide 1351 H 7-dimethylainino 1352 H 7-dimethylamino 1353 H 7-dimethylamino 1354 H 7-dimethylamino 1355 H 7-dimethylamino 1356 H 7-dimethylamino 1357 H 7-dimethylarmino 1358 H 7-dimethylamino 1359 H 7-dimethylamino 1360 H 7-dimethyl amino 1361 H 7-dimethylanmino 1362 H 7-dimethylamnino 1363 H 7-dimethylamino 1364 H 7-dimethylamino 1365 H 7-dimethylamino 1366 H 7-dimethylamino 1367 H 7-dimethylami'no ____1368 H 7-dimethylamino 1369 H 7-dimethylaniino 1370 H 7-dimethylamino 1371 H 7-dimethylarrino 1372 H 7-dimethylamino 1373 H 7-dimethylamnino 1374 H 7-dimethylamino 1375 H 7-dimethylamino 1376 H 7-dimethylamino 1377 A- H 7-dimethylamino ~1378 H 7-dimethylamino 1379 H 7-dimethylamino 1380 H 7-dimethylamino 1381 H 7-dimethylamino 1382 H 7-dimethylamino 1383 H 7-dimethylamino 1384 H 7-dimethylamino 1385 H 7-dimethylamino 1386 H 7-dimethylainino 1387 H 7-dimethylamnino 1388 H 7-dimethylamino 1389 H 7-dimethylamino 1390 H 7-dimethylamino 1391 H 7-dimethylamino 1392 H 7-dimethylamino 1393 H 7-dimethylamino 1394 H 7-dimethylaffino 1395 H 7-dimethylamino 1396 H 7-dimethylamino 1397 H 7-dimethylanuno 1398 H 7-dimethylamino 1399 H 7-dimethylamino 1400 H 7-dimethylamino 1401 H 7-dimethylamino 1402 H 7-dimethylamino 1403 H 7-dimethylamino 1404 H 7-dimethylamino 1405 H 7-dimethylamino 1406 H 7-dimethylamino 1407 H 7-dimethylarmino 1408 H 7-dimethylarnino 1409 H 7-dimethylan-dno 1410 H 7-dimethylamino 1411 H 7-dimethylamino 1412 H 7-dimethylamino 1413 H 7-dimethylarnino 1414 H 7-dimethylarnino 1415 H 7-dimethylamino 1416 H 7-dimethylamino 1417 H 7-dimethylamino 1418 H 7-dimethylamino 1419 H 7-dimethylamino 1420 H 7-dimethylamino 1421 H 7-dimethylamino 1422 H 7-dimethylan-dno 1423 H 7-dimethylamino 1424 H 7-dimethylamino 1425 H 7-dimethylamino 1426 H 7-dimethylamino 1427 H 7-dimethylamino 1428 H 7-dimethylamino 1429 H 7-dimethylanmino
I
1430 H 7-dimethylamino 1431 H 7-dimethylaniino 1432 H 7-dimethylamino 1433 H 7-dimethylan-ino 1434 H 7-dimethylamino 1435 H 7-dimethylamino 1436 H 7-dimethylamino 1437 H 7-dimethylamino 1438 H 7-dimethylamino 1439 H 7-dimethylamino 1440 H 7-dimethylanfino 1441 H 7-dimethylamino 1442 H 7-dimethylamino 1443 H 7-dimethylamino 1444 HI 7-dimethylamino 1445 H 7-dimethylarfino 1446 H 7-methoxy; 8-methoxy 1447 H 7-dimethylamino 1448 H 7-dimethylarnino 1449 H 7-dimethylamino 1450 H 7-dimethylamino 1451 H 7-dimethylamino WO 97/33882 PCT1JS97/04076 214 PEG 3400 molecular weight polyethylene glycol polymer chain H3C PEG 3400 molecular weight polyethylene glycol polymer chain SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 215
PEG
NH
0 00 $0 03C 0
N-CH
3
CH
3 02
JOOH
02 PEG 3400 molecular weight polyethylene glycol polymer chain SUBSITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 216
H
2
N
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 217 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 218 02 0 S
HOHN
SUBSTITUE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 219 SUBSTrITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 220 SUBS11TUTE SHEET (RULE 26) WO 97/33882 PTU9/47 PCTIUS97/04076 221 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 222 In further compounds of the present invention, R and R 6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium,
N-
alkylpiperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C to C 4 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, dioxyalkylene,
-[O(CH
2 where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R 5 or R 6 is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or disubstituted. Among the species which may constitute the substituents on the aryl ring of R 5 or R 6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R 5 or R 6 is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p- SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 223 hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, inmethoxyphenyl, p-N, N-dimethylaminopheriyl, rn-N, Ndime thyl aminophenyl, I p- (CH) 3 -N-phenyl, I- M- (CHi 3 3 phenyl, I- m- (CH 3 3 -N'-CH 2
CH
2 (OCH 2
CH
2 -0-phenyl, I-p- (CH 3 3 -N--CHCH,- (OCH 2 CH 2 2 phenyl, I- m- Ndimethylpiperaziniun) -CH 2 (OCH CH 2 2 phenyl, 3methoxy-4-fluorophenyl, thienyl-2 -yl, cholorothienyl-2-yl, 3,4-difluorophenyl, I- p- (N,Ndime thylp iperaz ini um) (OCHCH, 2 -O-phenyl, 3fluoro-4-inethoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3pyridinyl, N-rnethyl-4--pyr idiniun, I- N-methyl-3pyridinium, 3 .4-dioxymethylenephenyl, 3,4dioxyethylenephenyl, and p-niethoxycarbonylphenyl.
Preferred compounds include 3-ethyl-3-butyl and 3butyl-3-butyl compounds having each of the above preferred R5 substituents in combination with the Rx substituents shown in Table 1. It is particularly pref erred that one but not both of R' and R 6 is hydrogen.
It is especially preferred that R" and R 6 be hydrogen, that R 3 and R' not be hydrogen, and that R 3 and R 5 be oriented in the same direction relative to the plane of the molecule, both in a- or both in 9-configuration. It is further preferred that, where R 2is butyl and R1 is ethyl, then R" has the same orientation relative to the plane of the molecule asR3 and R 5 Set forth in Table 1A are lists of species of R 1/R 2
R
5 R and RX.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 224 Table IA: Alternativwe R Groups
RI/
(Rx)q R R 6
R
1
R
2 ethyl fl-propyl n-bu tyl n-pentyl n-hexyl iso-propyl iso-butyl iso-pentyl
CH
2 C (=0)C 2
H
5
CH
2 0C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 O- (4-picoline)
R
3
R
4
HO-
R
5 Php-F-Phrn-F-Php-C- 3 0- Php-CH 3 0- Phm-CH 3 O- Php- (OH 3 2 N-Phin- (OH 3 2 N-Ph- Pn- (CH 3 3 -NW-Php- (CH 3 3
-N+-CH
2 CHi 2
(OCH
2
CH
2 2 Phm- (CH 3 3
-N+-OH
2
CH
2
(OCH
2
CH
2 2 -0-Ph- P- Ndimethylpiperazine)
-CH
2
(OCH
2
CH
2 20 Phdimethylpiperaziie)
-OH
2
(OCH
2
CH
2 2 -0- Phrn-F, p-CH 3 O-Ph- 3, 4, dioxyinethylene- Ph in-CH 3 p-F-Ph- 4-pyridine N-methyl-4-pyridinium, I- 3 -pyridine N-inethyl-3-pyz-idinium, I- 2 -pyridine
P-CH
3
O
2 C-Phthienyl-2-yl 5-Cl-thienyl-2-yl WR) q 7-methyl 7-ethyl 7-is 0-propyl 7-tert-butyl 7-OH 7-OCH 3 7-SCH 3 7-SOCH 3 7-SO 2
CH
3 7-SCH 2
CH
3 7-NH 2 7-NHOH 7-NHCH 3 7-N(CH 3 2 7-N'(CH 3 3
I-
7 -NHC (=0)OH 3 7-N(CH 2
CH
3 2 7-NMeCH 2 00 2
H
7-Nt (Me) 2 CHi 2 C0 2 H, I- 7- -morpholine 7-M()-azetidine 7- -N-inethylazetidinium,
I-
7- -pyrrolidiie 7- -N-methylpyrrolidinium, I- 7- -N-methylmorpholiniun, I- 7- (N)-N'-methylpiperazine dimethylpiperaziniun,
I-
7-NH-CBZ 7-NHC (0)C 5 Hjj 7-NHC (0)CH 2 Br 7-NH-C (NH)NH 2 7-M()-thiophene continued next page...
SUBSTITUJTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 225
R
1
R
2
R
3
R
4
R
5 WR) q 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8 -OH
B-OCH
3 8-aC iso-propyl) 8- SCH 3 8-SOCH 3 8-SO 2
CH
3 8-SCH 2
CH
3 8-NH 2 8-NHOH 8-NHCH 3 8-N(CH 3 2 8-N 4
(CH
3 3
I-
8-NHC CH 3 8-Nq (CH 2
CH
3 2 8 -NMeCH 2
CO
2
H
8-N+(Me) 2
CH
2
CO
2 H, I- 8-M()-morpholine 8-M()-azetidine 8-M()-N-methylazetidinium,
I-
8-M()-pyrrolidine 8- -N-methylpyrrolidinium, I- 8- -N-methylmorpholinium, I- -rethylpiperazine 8- dimethylpiperazinium,
I-
S -NH-CBZ 8-NHC (0)C 5 Hll 8-NHC (0)CH 2 Br 8-NH-C (NH) NH 2 -thiophene continued next page...
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PC.T1US97/04076 226
R
2
R
3
R
4 RS q 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH 3 9-O(iso-propyl) 9-SCH 3 9-SOCH 3 9-SOCH 3 9 -SCH 2
CH
3 9-NH 2 9-NHOH 9 -NHCH- 3 9-N(CH 3 2 9-N*(CH 3 3
I-
9-NHC (=O)CH 3 9-N (CHCH 3 2 9 -NMeCH 2
CO
2
H
9-N*(Me) 2
CHCO
2 H, I- 9-M()-morpholine 9- -azetidine 9- -N-methylazetidinium,
I-
9- -pyrrolidine 9-M()-N-methylpyrrolidinium, I- 9- -N-methylmorpholinium, I- -methylpiperazine 9- dimethylpiperazinium, 9-NH-CBZ 9 -NHiC C 5 H 1 9-NHC (O)CH 2 Br 9-NH-C (NH)NH 2 9- -thiophene 7-OCH 3 8-OCH 3 7-SCH 3 B-0CH 3 7-SCH 3 8-SCH 3 3 7-0CH 3 8-OCH 3 Further preferred compounds of the present invention comprise a core structure having two or more Pharmaceutically active benzothiepirie structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise: SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 227 (0
R
7 (RXS 8 P6 4 (Formula DIV) or:
R
7 S 88
(R
(Formula DIVA) where R 2 R 4 R 6
R
5
R
6
R
7
R
8 X, q and n are as defined above, and R" 5 is either a covalent bond or arylene.
The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by 0, NR 7 N*R 7R", S, SO, S02, S*R R PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 SUBSTTTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 228 131 313 13 13 13 14
NR
13
R
1
SR
13 S(O)R ,S02R ,S03R ,NR OR
NR
13
NR
14
R
1 N02, C02R' 3 CN, OM, S020MN S02NR 13
R
1
CON
13
R
14 C()M 0 13
P()
13 1 4 13 14 C(ONR CO)O, CR P()RR ,PR R P (OR 3 )OR SR 3 R and N +R 9 R11 R12 A-; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups 7 7 8 7 selected from the group consisting of OR NR R SR 7 7 7 7 7 8 78 9 S(O)R S02R S03R C02R CN, oxo, CONR R N R R R Aalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, 7 8 p +78 P(O)R R PR R A and P (OR)OR', and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR7 N +R 7R 8A-, S, SO, S02, S +R 7A-, PR 7, P P R 7R 8A-, or phenylene.
Exemplary core moieties include: 26 R 2 27 26 o2
R
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/EJS97/04076 229 26 27 R 2 8 R 2 6 0 10, 27 ~2k 2 R27 R k wherein: R 25 is selected from the group consisting of C and N, and R 26and R" are independently selected from the group consisting of: SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 230
R
S (0)
-CH
2 R31
N
0 G-- 0
II
C k
S
I I C
O
II-
C -O,
S
II
R
3 1 -Si-, 3 2 -NH -NH
-NHSO
2 and NH
A"\NH
2 wherein R 2
R"
9 R" and R 31 are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl, A- is a pharmaceutically acceptable anion, and k 1 to In compounds of Formula DIV, R 2 0
R
21
R
2 in Formulae DII and DIII, and R 2 3 in Formula DIII can be bonded at any of their or 9- positions to R 9 In compounds of Formula DIVA, it is preferred that R 55 comprises a phenylene moiety bonded at a m- or p-position thereof to R".
In another embodiment, a core moiety backbone, R' 9 as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, R 2
R
21 R and R" as discussed above, through multiple functional groups within the core moiety backbone.
suBsmWE SEET (RLE 26) WO 97/33882 PCT/US97/04076 231 The core moiety backbone unit, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. .Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R 9 The more preferred benzothiepine moieties comprising
R
2
R
2 R" and/or R" conform to the preferred structures as outlined above for Formula I. The 3-carbon on each benzothiepine moiety can be achiral, and the substituents R R 2
R
3
R
4 R' and Rx can be selected from the preferred groups and combinations of substituents as discussed above.
The core structures can comprise, for example, poly(exyalkylene) or oligo(oxyalkylene), especially poly- or oligo(exyethylene) or poly- or oligo(oxypropylene).
Dosages, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, a human.
For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se. Pharmaceutically SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 232 acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.
The anions of the definition of A- in the present invention are, of course, also required to be pharmaceutically acceptable and-are also selected from the above list.
The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unitdose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 233 These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.
The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.
In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day.. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.
Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.
Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 234 The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention.
Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be convenientlyadministered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.
Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal sublingual), and parenteral subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 235 invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a freeflowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sublingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert-base suchas gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 236 contain from 0.1 to 5% w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with ono or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.
Transdermal administration is also possible.
Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 318 (1986).
In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 237 sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable carriers encompass all the foregoing and the like.
Treatment Regimen The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, atherosclerosis, or to protect SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 238 against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 239 The following non-limiting examples serve to illustrate various aspects of the present invention.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 240 EXAMPLES OF SYNTHETIC PROCEDURES Preparation 1 2-Ethyl-2-(mesyloxymethyl)hexanal (1)
O
II
o 2 CH3SO, O CH2 S
H
1 To a cold (10 OC) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2- (hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30 The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 24.4 g of brown oil.
Preparation 2 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTfEJS97/04076 241 A mixture of 31 g (0.144 inol) of 2nercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2- (mesyloxymethyl)-hexanal 14.8 g (0.146 mole) of triethylamine, and 80 xnL of 2-methoxyethyl ether was held at ref lux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO 4 and concentrated in vacua to remove 2methoxyethyl ether. The residue was purified by HPLC EtOAc-hexane) to give 20.5 g of 2 as an oil.
Example 1 3 -Butyl-3 -ethyl 5-phenyl-2, 3 -dihydrobenzothiepine cisB-3 -Butyl-3 -ethyl -5 -phenlyl- 2, 3 -dihydrobenzothiepin- (5H) 4 one (4a) and trans-3 -Butyl-3 -ethyl- 5-phenyl-2, 3 -dihydrobenzothiepin- (SH)4-one (4b) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl 3 and 80 xnL of anhydrous ethylene glycol SUBSilUF SHEET (rigUL 26 WO 97/33882 PCT/US97/04076 242 dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5 To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g of 4a in the earlier fraction and 0.1 g of 4b in the later fraction.
Example 2 cis-3-Butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzothiepin- (5H)4-one-1,1-dioxide (5a) and trans-3-Butyl-3-ethyl-5phenyl-2,3-dihydro-benzothiepin- (5H)4-one-, 1-dioxide Sb To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in mL of methylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO,, and concentrated in SUBSTUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 243 vacuo. The residual syrup was purified by H-PLC EtOAchexane) to give 0.2 g (30%)of Sa as an oil in the first fraction and 0.17 g of 5b as an oil in the second fraction.
Example 3 (3a,4L,53) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1,1:-dioxiLde (3ct,4J3, 5a) 3- Butyl-3-ethyl-4-hydroxy-5-phenyl-2, 3,4, benzothiepine- 1, 1-dioxide (3a,4cx,5a) 3 -Butyl--3-ethyl- 4-hydroxy-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3at,403,50) 3 -Butyl -3 -ethyl -4-hydroxy- phenyl 3, 4, 5 ttrahydrobenzothi epine 1 -dioxide (6d)
OH
6a
OH
6C A. Reduction of 5a and 5b with Sodium Borohydride To a solution of 0.22 g (0.59 rcuole) of 5b in 10 znL of ethanol was added 0.24 g (6.4 nmole) of sodium borohydride.
The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue SUBSITUTE SHEET (RULE- 26) WO 97/33882 PCT/US97/04076 244 was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g of 6a as a syrup. The second fraction was 0.2 g of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g of 6c in the third fraction as a solid.
Recrystallization from hexane gave a solid, mp 179-181 oC.
Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g of 6d in the fourth fraction as a solid.
Recrystallization from hexane gave a solid, mp 160-161 OC.
B. Conversion of 6a to 6c and 6d with NaOH and PTC To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CHC1 2 was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of icecrystals then was extracted with CH,C1 2 (3x10 ml), dried over MgSO 4 and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg of 2-(2-benzylphenylsulfonylmethyl)-2ethylhexenal in the first fraction, 30.9 mg of 6c in the second fraction and 90.0 mg of 6d in the third fraction.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 245 Oxidation of 6a to To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of
CH
2 C1 2 was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH,C1,. The filtrate was concentrated in vacuo to recover 167 mg of 5b as a colorless oil.
Example 4 3-Butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzothiepine-, 1dioxide (7) SO2 7 To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of
CH
2 ,Clwas added 10 g (31.9 mmole)of 50-60% MCPBA (mchloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N, and was triturated with mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH 2 C1 2 (4x20 mL). The CHC1, extract was dried over MgSO, and evaporated to dryness to recover 4.9 g of an opaque viscous oil.
Example (laa,23,8ba 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8btetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 246 (laL, 2a, Bbc) 2-Butyl-2 -ethyl- Sb-phenyl-la, 2, 3, Bb-tetrahydrobenzothiepino [4,5 oxirene-4, 4-dioxiLde (8b) 8a 8b To 1. 3 g 03 mole) of 3 in 25 rnL of CHCl 3 was added portionwise 5 g (14. 1 mmole) of 50-60 MCPBA causing a mild exotherm. The reaction mixture was stirred under N, overnight and was then held at ref lux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50* mL) once with brine, dried over MgSO 4 and concentrated in vacuo to give 1 .37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg of a white crystalline product.
This isomer was characterized by NNR and mass spectra to be the (lac,2f3,8ba) isomer Ba. The hexane filtrate was concentrated in vacuo to give 2 06 mg of white film which is a mixture of 30% Ba and 70% 8b by 'H NMVR.
Exampl1e 6 c i s- 3-Butyl ethyl 5-phenyl 3, 4, 5 -tet rahydro benzothiepjne- 1, 1 -dioxide trans-3-Butyl-3-ethyl-5phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide and 3 -Buty- 3ethyl.-4 hydroxy.5.cycloheyldne.. 3, 4, tetrahydrobenzothiepine-1, 1-dioxide SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 247 9b 9a 10 A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.l.g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H, for 5 h and filtered.
The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg of 9b.. The second fraction, 5.0 mg was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg of 6a The fourth fraction was 25.5 mg of 6b. The fifth fraction was 9.6 mg of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg of a mixture of 6d and one of the isomers of 10, Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHC1, under air was hydrogenated in 100 mL of methanol using 1 g of Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g of 9b, 0.45 g of 9a, 0.27 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 248 g of 6a, 0.51 g of 6b, 0.02 g of 6c, 0.06 g of one isomer of 10, 10a and 0.03 g of another isomer of 10, Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) S CH 2 O
H
O
11 To an ice bath cooled solution of 9.76 g (0.116 mole of 2 -ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days diluted with ether, and was washed successively with dilute HC1, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 OC) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.
Example 9 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 249
S
12 To a mixture of 2.61 g (0.04 mole) of zinc dust and mL of DME was added 7.5 g (0.048 mole) of TiC1,. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO, and concentrated.
The residual oil (2.5 g) was purified by HPLC to give 2.06 g of 12 as an oil in the second fraction.
Example (laa,2a,8ba) 2-Ethyl-8b-phenyl-la,2,3,8b-tetrahydrobenzothiepino-[4,5-b]oxirene-4,4-dioxide (13) S02 0 2 13 To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHC1, was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K 2 CO, (4x50 ml), water (twice with SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 250 ml) and brine. The organic layer was then dried over MgSo, and evaporated to dryness to recover 1. 47 g of an of f white solid. 'H NMR indicated that only one isomer is present.
This solid was slurried in 200 ml of warm Et,O and filtered to give 0.82 g of 13 as a whitersolid, mp 185-186.5 0C.
(3a,4P,5a)- 3 -Ethyl -4 -hydroxy- 5-phenyl-2, 3,4, tetrahydro-benzothiepine-1, 1-dioxiLde (14a), (3a,43, 5j3) 3- Ethyl -4 -hydroxy- 5-phenyl 3, 4, 5 -t etrahydrobenzothiepine..
1,1-dioxide (14b), and cis- 3-Ethyl,- 5-phenyl-2, 3,4, tetrahydro-benzothiepine-l, 1-dioxide O H 14a O H 14b A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO 3 solution followed by 89 g of NaHCO 3 powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 ml), then the SUBSTTUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 251 organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg of in the first fraction, 272 mg of 14a as a solid, mp 142-143.5 oC, in the second fraction, and 35 mg of impure 14b in the third fraction.
Example 12 2-Ethyl-2-((2 -Hydroxymethylphenyl) thiomethyl)hexenal (16) S "CH2 OH H
OH
16 A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HC1 and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residue.
Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil.
Example 13 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 252 S YCH2 O
H
-H
H
0 17 A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.
Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)
S
18 A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiC1 3 and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HC1 and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g of 18 as an oil in the early fraction.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 253 Example (laa,2a,8ba 2-Butyl-2-ethyl-la,2,3,8b-tetrahydrobenzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and (laa,20,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b-tetrahydrooxirene-4,4-dioxide (19b)
S
0 2 S02 0 0 19a 19b To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in mL of methylene chloride was added 2.2 g (3.2 mmole) of 60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHC1, and was held at reflux for 18 h under The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC EtOAc-hexane) to give 0.12 g of syrup in the first fraction.
Recrystallization from hexane gave 0.08 g of 19a, mp 89.5-105.5 OC. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.
Example 16 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5tetrahydro-benzothiepine-1,1-dioxide SUBSTUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 254
S
0 2 H OH This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.
Example 17 3 -Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5tetrahydro-benzothiepine-1, -dioxide (21) SO2
OH
21 A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N, for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO,, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by H NMR and mass spectra.
SUBSTTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 255 Example 18 Alternative Synthesis of 6c and 6d A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2ethylhexanal (2) Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2ethylhexanal (44)
SO
2 OO0 H I 44 To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136 °C Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2ethylhexanal SUBSTIfTE SIEET (RULE 26) WO 97/33882 PCT/US97/04076 256
SO
O H A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.
Step 3. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and (3a,4p,5p) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (6d) To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 OC with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of HC1 and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil.
Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g of 6c in the second fraction and 6.5 g of 6d in the third fraction.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 257 B. Preparation from 2-hydroxydiphenylmethane Step 1. 2-mercaptodiphenylmethane (46)
SH
46 To a 500 ml flask was charged 16 g (0.33 mol) of sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30 oC by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280- 300 OC in a kugelrohhr pot under house vacuum for 30 min.
The residue was kugelrohr distilled at 1 torr (180-280 OC).
The distillate (56.3 g) was crystallized from methanol to give 37.3 g of the rearranged product dimethyl S-2benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTUS97/04076 258 made acidic with concentrate HC1, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g of 2mercaptodiphenylmethane as a yellow solid.
Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)
S
0 H 47 A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2 2 -benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.
Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2ethylhexanal SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/IJS97/04076 259 S02 0 H To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 'C was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of benzylphenylsulfonyl )methyl) -2-ethylhexanal 45 as a syrup.
Step 4. (3a,4a, 5a) 3 -Butyl-3 -ethyl -4 -hydroxy-5 -phenyl- 2, 3 F4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide and (30L,4J3,5J0) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1, 1-dioxide (6d) Reaction of 45 with potassium t-butoxide, according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC.
Examp~le 19 (3ct,43, 5p) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5- Phenyl-2, 3, 4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide (25) and (3xL,4z, Sc) 3 -Butyl 3-ethyl -4 -hydroxy- 8-methoxy- 5-phenyl 2, 3,4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide (26) Step 1. Preparation of 2- -benzoyl-4 -methoxy phenylthio)methyl) -2-ethyihexanal (22) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 260
H
S
0
H
3 C.1 22 2 -Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed.
The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 °C as previously described. The improved isolation procedure which avoided a chromatography step was described below.
The crude pyrolysis product was then heated at 65 OC in 100 ml of methanol and 100 ml of THF in the presence of g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5 NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2 -mercapto-4-methoxybenzophenone (2.3 g) was isolated.
2 -mercapto-4-methoxybenzophenone can readily be converted to the 2-((2-benzoyl-4-methoxyphenylthio)methyl)- 2 -ethylhexanal (22) by reaction with 2-ethyl-2- (mesyloxymethyl)hexanal as previously described.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTfUS97/04076 261 Step 2. 2- ((2-Benzoyl-5-methoxyphenylsulfonyl)methyl) 2-ethyihexanal (23)
H
3 CO S-CH, 0 23 Substrate 22 was readily oxidized to 2-((2-benzoyl-5methoxyphenyl-sulfonyl )methyl) -2 -ethylhexanal (23) as described in example 18.
Step 3. 2- ((2-benzyl-5-methoxyphenylsulfonyl )methyl) -2ethyihexanal (24) Suif one 23 was then reduced to 2-((2-benzyl-5methoxyphenyl-sulfonyl )methyl) -2-ethylhexanal (24) as described in example 18.
Step 4. (3a,4J3, 5P) 3 -Butyl -3 -ethyl -4 -hydroxy-B8-methoxy- -Phenyl 3, 4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 262 and (3a,4a,5a) 3 -Butyl- 3 -ethyl-4-hydroxy-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) CHO,
/SO,
OH
O H S H 26 A 3-neck flask equipped with a powder addition funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 OC internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide. by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 °C.
After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10 HC1. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.
The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 OC. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 263 addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.
Example (3c,4ac, 5C) 3-Butyl-3-ethyl-4, 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (27) HO S02
OH
I 2 7 In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 ml methylene chloride were cooled to 78 OC with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCI and then water.The organic layer was dried over magnesium sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.
Example 21 General Alkylation of phenol 27 A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole).
The reaction was stirred at room temperature overnight.The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 264 stripping of f the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NmR and mass spectra.
This same procedure was used to prepare products listed in table 1 f rom the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.
Formula f or Table 1 Compound No.
27 26 28 29 31 Table 1
R
H
Me Et hexyl Ac (CHi2) 6-N-pthalimide Ex=ample 2 2 (3z, 4a, 5c) 3 -Butyl -3 -ethyl 4-hydroxy-7 -hydroxyamino-5 phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (37) and (3a,403,503) 3 -Butyl -3 -ethyl -4 -hydroxy 7-hydroxyamino-5 phenyl 3, 4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide (38) Step 1. Preparation of (32) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 265 Cl
NO
2 32 Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah.G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps( trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed- to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and combined with two 500 ml methylene chloride extractions of the aqueous layer.
The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.
Step 2. Preparation of 2-((2-benzyl-4nitrophenylthio)methyl)-2-ethylhexanal (33) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 266
NO
2
S
O H 33 The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75 OC for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in ml DMSO. The reaction mixture was heated to 80 OC under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary. Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgSO4. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5 ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.
Step 3. Oxidation of the nitro product 33 to the sulfone 2- ((2-benzyl-4-nitrophenylsulfonyl)methyl)-2ethylhexanal (34) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 267
NO
2 S02 0
H
34 The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.
Step 4. Reduction of 34 to 2-((2-benzyl-4hydroxyaminophenylsulfonyl) methyl) -2-ethylhexanal HONH-- S02 O
H
A 15 g sample of 34 was dissolved in 230-ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc.
Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.
Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(tbutoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl) -2ethylhexanal (36).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 268 C H 3
H
3
C-C-CH
3 I0
OH
3 0 1 11 C~o 0
H
3 C-C-O-C ONS0
OH
3 O
H
36 A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry TI-F was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60 'C overnight. Striped of f TH-F and redissolved in methylene chloride. Extracted with 1. H~l; and then 5% sodium bicarbonate.
The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-(tbutoxycarbonyl) derivatives by proton NMR.
Step 6. (3c,4a, 5c) 3-Butyl-3-ethyl-4-hydroxy-7hydroxyazujno-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide (37) and (3a,4j3, 5f) 3-Butyl-3-ethyl-4-hydroxy-7hydroxyvamino-5-phenyl-2, 3,4, 5-tetrahydrobnzothiepine-., 1dioxide (38) S0 2
HONH
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 269
SO
2
HONH-
S OH 38 A 250ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 OC under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with stirring and maintaining a -78 OC reaction temperature. After 1 h at -78 °C the addition of base was completed and the temperature was brought to -10 OC by means of a ice/salt bath. After 3 h at -10 only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10 °C and stirred for 5 min. Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g).
Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1 (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97104076 270 Example 23 (3cx,4ot,5cx) 3 -Butyl-3 -ethyl (n-hexylazaino) -4-hydroxy- 5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide and (3a,4P,5P) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (41) Step 1. 2-((2-Benzyl-4-(nhexylamino)phenylsulfonyl)methyl) -2 -ethyihexanal (39) NH- S0 2 39 In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 inmoles) and dissolved in 3.8 ml of ethanol under nitrogen.
Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate.
The product was characterized by NMR and mass spectra.
Step 2. (3a,4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4hydroxy-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide and (3i, 43, 5P) 3-Butyl-3-ethyl-7- (n-hexylamino) -4hydroxy-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (41) SUBSMMUT SHEET (RULE 26) WO 97/33882 PCTIS97/04076 271 SO2 /S02 OH OH.
41 A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to -10 oC by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10 OC all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HC1 and stirred at OC for 5 min. Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 53.2 mg); 41(58.9 mg).
Example 24 Quaternization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.
Example (3a,40,5p) 3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (42) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 272
SO
2
SOH-
42 In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d ,0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; ml of saturated KI and dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F.
Et al.Mass spectrum indicated a mixture of 6d mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass spectra.
Example 26 (3a,4,5p) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4hydroxy-2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (43) S02 0 43 o=c
OCH
3 A 0.1 g sample of 42 0.212 mmole), 2.5 ml dry SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 273 methanol, 38 p1 triethylamine (0.275 nunole) 0.3 ml toluene and 37 mg of palladium chloride (0.21 mniole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 00 overnight. The catalyst was filtered and a high yield of product was isolated.
The product was characterized by NMR and mass spectra.
Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.
Example 27 (3a,4a, 5a) 3 -Butyl- 3-ethyl -4-hydroxy-7 -methoxy- phenyl- 2, 3, 4, 5 -tetrahyVdrobenzothiepine 1- dioxide and (3L, 413, 5j) 3 -Butyl- 3-ethyl -4-hydroxy-7 -methoxy-5 -phenl 2,3,4, 5-tetrahydrobenzothiepile-1, 1-dioxide (49) Step 1. 2-Mercapto-5-methoybenzophelofe OCH3 Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithiun, 105 g of tetramethylethylenediane and 66.7 g of benzonitrile in 600 mil cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythioPhelol and gave 43.86 g of crude 50 in the pot residue.
Step 2. 2- ((2-Benzoyl-4-methoxyphenylthio)methyl) -2ethylhexana1 (51) SUBST1TUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 274
H
3
C
Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC ethyl acetate-hexane) to give 1.7 g of 51.
Step 3. 2- ((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyl-hexanal (52)
H
0 \O \s 52 A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g of 52 as a yellow oil.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 275 Step 4. 2- ((2-Benzyl-4-methoxyphenylsulfonyl )methyl) 2-ethyihexanal (53) Hydrogenation of 1. 1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil 1 g) Step 5. (3ct,4a, 5a) 3 -Butyl- 3-ethyl -4 -hydroxy-7 -methoxy- 3, 4, 5 -tetrahydrobenzothiepine-1, 1 -dioxide (48), and (3az,403,50) 3 -Butyl- 3-ethyl -4 -hydrox-y-7 -methoxy-5 -phenyl 2,3,4, 5-tetrahydrobenzothiepine-.,1-dioxide (49)
CH
3 0 A solution of 1.1 g of 53, 0.36 g of potassium tbutoxide and 25 ml of anhydrous THF was held at -ref lux for 2 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 276 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg of 48 as crystals, mp 153-154 OC and 90 mg of 49 as solid, mp 136-140 °C.
Example 28 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57) Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)
S
OH
oH 57 54 To a cold (OC'mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol.
The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g of thick oil. Proton NMR and mass spectra were consistent with the product.
Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 277
O
II
OSCH
3
II
OC H
O
To a cold (0°C'mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HC1 and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g of thick oil. Proton NMR and mass spectra were consistent with the product.
Step 3. Benzoylphenylthio) methyl)cyclohexanecarboxaldehyde (56)
S
O
H
0 S 56 A mixture of 69 g (0.303 mole) of 2mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil.
HC1 and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 278 EtOAc: Hexane) and gave 18.6 g of yellow oil.
Proton NMR and mass spectra were consistent with the product.
Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'cyclohexane (57)
S
ll 57 To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiC1,(16.8 g, 0.108 mole) The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91 C. Proton and carbon NMR and mass spectra were consistent with the product.
Example 29 8b-Phenyl-la,2,3,8b-tetrahydrospiro b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 279 Y 58 To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. This was recrystallized from Hexane/EtOAc to give 4.31 g of yellow solid, mp 154- 155 C. Proton and carbon NMR and mass spectra were consistent with the product.
Example trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-l,1-dioxide (59) SO2
OH
A mixture of 0.5 g (1.4 mmoles) of 58 20 ml of ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg as a white solid, mp 99-100 C. Proton NMR showed this was a trans isomer. The second SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 280 fraction gave 200 mg of solid which was impure cis isomer.
Examtole 31 cis-4-Hydroxy-5-phenyl-2, 3,4, spiro(benzothiepine-3, 1'-cyclohexane) 1-dioxide To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH 2 Cl 2 was added 8 g of 50% NaOH and one drop of Aliquat-336 (me thyl tri caprylyl ammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH 2 C1 2 (3x10 ml) washed with water, brine and dried over MgSO, and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209- 210 C Proton and carbon WAR and mass spectra were consistent with the product.
Examle 32 (3cu,4cL,5cx) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine and (3a,43,50) 3-Eutyl-3ethyl 4-hydroxy- 5-phenyl 3, 4, 5 -tet rahydrobenzothiepine (62) SUBSTITUTE SHEET (RULE 26) sU8ftakjj khW (RLtE26 WO 97/33882 PCTIUS97/04076 281 S S OH OH 61 I62 To a solution of 0.5 g (1.47 imole) of compound 47 in ml of anhydrous TEF was added 0. 17 g 47 mmole) of potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of HC1. The organic was extracted into methylene chloride. The mnethylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.
Examiple 33 (3a,4t, ScL) 3 -Butyl 3ethyl -4 -hydwoxy-7 -amino- 5-phenyl 2,3,4, 5-tetrahiydrobenzothispine-2.,1-dioxide (63) and (3cx,40, 5p) 3 -Butyl- 3-ethyl -4 -hydroxy-7 -amnino- 5-phenyl 2, 3, 4,5 tetrahydrobenzothiepine- 1, 1-dioxide (64) 63 SUBSTIUT SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 282
SO
2
NH
2
-OH
64 An autoclave was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55 C.
The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63. This same procedure was used to produce 64 from 38.
Examle 34 (3ai,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- methoxyphenyl) 5-tetrahydxobenzothiepine-1, 1-dioxide and (3c4J,53) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (3 '-methoxyphenyl) 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide (66).
OH
OCH
3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 283 S0 2
CH
3 0
OH
66
OCH
3 Alkylation of e-niethoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-methoxy-2 (-methoxybenzyl) phenol in 35% yield. This material was converted to compound nip 138.5-141.5 and compound 66, mp, 115.5-117.5 by the procedure similar to that in Example 18 method B.
Examiple (3c,4L, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (trifluoromethy phonyl) 1,1-dioxide and (3ct,4j3,51) 3-Butyl-3-ethyl-4-hydroxy- (trifluoromethyl)phenyl) -2,3,4,5tetrahydrobenzothiepine-1, 1-dioxide (68).
CF
3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 284
CH
3 0
-OH
CF
3 __o6 Alkylation of 4-inethoxyphenol with 3- (trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy--2-(31- (trif luoromethyl) benzyl) phenol. This material was converted to compound 67, mp 226.5-228 and compound 68, mp 188- 190'C, byu the procedure similar to that in Example 18 method B.
Examrle 36 (3oL,4cx,5a) 3-Butyl-3-ethyl-5- -fluorophenyl)-4hydroxy-7 -methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3cL,413,51) 3-Butyl-3-ethyl-5-(41fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5tetrahydrobenzothiepine-1, 1-dioxide 02 0 F 69 F Alkylation of 4-methoxyphenol with 4-f luorobenzyl chloride according to the procedure described in J. Chemn.
Soc, 2431 (1958) gave 4-methoxy--2-(4 1-f luorobenzyl) phenol.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 285 This material was converted to compound 69 and compound by the procedure similar to that in Example 18 method B.
Example 37 (3ci,4a,5a) 3-Eutyl-3-ethyl-5-(3 '-fluorophenyl)-4hydroxy-7 -methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3aL,4p,53) 3-Butyl-3-ethyl-5-(3'fluoropheiyl) -4-hydroxy-7 -methoxy-2, 3,4,5tetrahydrobenzothiepine-1, 1-dioxide (72).
S S H3CO
H
3
CO
H 1OH 71 72 Alkylation of 4-methoxyphenol with 3-f luorobenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-methoxy-2- (3 1 -f luorobenzyl) phenol.
This material was converted to compound 71 and compound 72 by the procedure similar to that in Exarnple 18 method B.
Example 38 (3oa,4c,5a) 3-Butyl-3-ethyl-5-(2 '-fluorophenyl) -4hYdroxy-7-methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3cz,4J3,5P) 3-Butyl-3-ethyl-5-(2'fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5tetrahydrobenzothiepine-1, 1-dioxide (74).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 286 S S H3CO
H
3
CO
H F b 73 74 Alkylation of 4-methoxyphenol with 2-f luorobenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-methoxy-2 luorobenzyl) phenol.
This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.
Examrole-39 (3ic,4a,5aL) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3 1methoxyphenyl) 3, 4, 5 -tetrahydrobeazothiepine- 1, 1 -dioxide and (3a,43,5) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5- (3 1-methoxyphenyl) 3,4, 5-tetrahydrobenzothiepine-1, Idioxide (76).
S S Br OH OCH3
IOCH
3 76 Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-bromo-2- (3 1-methoxybenzyl) phenol.
This material was converted to compound 75, xnp 97-101.5 *C, SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 287 and compound 76, mp 102-106 Oc, by the procedure similar to that in Example 18 method B.
Examiple (3a,4a,5t) 3-Butyl-3-ethyl-7-fluoro-5-(4'fluorophenyl) -4-hydroxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,40,503) 3-Butyl--3-ethyl-7-fluoro-5-(4'f luorophenyl) -4-hydroxy-2, 3,4, 5-tetrahydrobenzothiepine-1, Idioxide (78).
S S
F
H 'OH
FF
77 78 Alkylation of 4-fluorophenol with 4-f luorobenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-fluoro-2-(4 '-fluorobenzyl)phenol.
This material was converted to compound 77, nip 228-230 'C, and compound 78, nip 134.5-139 0 C, by the procedure similar to that in Example 18 method B.
Examp~le 41 (3z,4cx, 5a) 3-Buty1-3-ethy1-7-fluoro-4-hydroxy-5- methoxyphenyl) 5-tetrahydrobeuzothiepine-1, 1-dioxide and (3a,403,503) 3-Butyl-3-ethy:L-7-fluoro-4Ohydroxy-5- (3 '-methoxyphenyl) 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide SUBSTITUITE SHEET (RULE 26) WO 97/33882 PCTIEJS97/04076 288 /Y Alkylation of 4-fluoropheiol with 3-methoxybenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-f luoro-2 -(31 -rethoxybenzyl) phenol.
This material was converted to compound 79, as a solid and compound 80, mp, 153-155 0 C, by the procedure similar to that in Example 18 method B.
Exam-Ple 42 .0 (3c1,4J,5p) 3-Butyl-3-ethyl-5-(4 '-fluorophenyl)-4hydroxy-7 -methylthio-2, 3,4, 5-tetrahydrobenzothipiie-1, 1dioxide (81).
A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction SUBMMTT SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 289 mixture was dilute with ether and washed with water and brine and dried over MgSO,. The ether solution was concentrated in vacuo. The residue was purified by HPLC ethyl acetate in hexanes) The first fraction was impure (3a,4cx,5a) 3-butyl-3 -ethyl -4-hydroxy-7 (4'-fluorophenyl) -2,3,4,5-tetrahydrobenzothiepine-1,1dioxide. The second fraction was compound 81, mp 185-186.5 0C.
Examrple 43 (3cL,4J,513) 3 -Butyl-3 -ethyl- 5 1 -f luorophenyl) -4hydroxy-7 -(1-pyrrolidinyl) 1,1-dioxide (82).
02
S
C7- 82 A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over MgSO 4 The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177 *C.
SUBS1TTT SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 290 Example 44 (3a,43,5f) 3-Butyl-3-ethyl-5-(4 '-fluorophenyl)-4hydroxy-7 -(1-morpholinyl) 3,4, 1,1-dioxide (83).
02
S
0
OH-
83 A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at ref lux for 2 h and concentrated in vacuc. The residue was diluted with ether ml) and washed with water and brine and dried over MgSO 4 The ether solution was concentrated in vacuc. The residue was recrystallized from ether-hexanes to give compound 83, mp 176.5-187.5 0
C.
Example (3a,4cx, 5a) 3-Butyl-3-ethyl-5-(4 '-fluorophenyl) -4hydroxy-7 -methyl-2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide and (3cL,4J,5J3) 3-Butyl-3-ethy3l-5-(4'-fluorophelyl)-4hydroxy-7-methyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide SUBSTITUTE SHEET (RULE 26) WO 97/33892 PCT/IJS97/04076 291 S S H3C H 3
C
H 'OH
FF
84 Alkylation of 4-methyiphenol with 4-f luorobenzyl chloride according to the procedure described in J. Chem.
Soc, 2431 (1958) gave 4-methyl--2- (4 luorobenzyl) phenol) This material was converted to compound 84 and compound by the procedure similar to that in Example 18 method B.
Example 46 (3z, 43, 513) 3 -Butyl-3 -ethyl -4-hydroxy-5- (41 hydroxyphenyl) -7-methoxy-2, 3,4, 1,1-dioxide and (3cz,4J,513) 3-Butyl-3-ethyl-4,7- (4 '-hy droxyphenyl) -2,3,4,5tetrahydrobenzothiepine-1, 1-dioxide (87).
02 021 S
S
H
I
H
3 CO
HO
b H HO
HO
86 87 To a solution of 0.52 (1.2 mmol) of compound 66 in ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to -78 0 C and SUBSTITUTE S.HEET (RULE 26) WO 97/33882 PCT/US97/04076 292 was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at 78 OC for 1 h and quenced with 2 N HC1. The organic was extracted into ether. The ether layer was washed with brine, dried over M SO., and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173 OC.
The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264 OC (dec) Example 47 (3a,40,5p) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'fluorophenyl) -2,3,4,5-tetrahydrobenzothiepine-l, 1-dioxide (88).
02
S
HO
OH
F
88 Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.
Example 4 8 (3a, 40,5p) 3-Butyl-3-ethyl- 5 (4 -fluorophenyl) -4hydroxy-7 (1-azetidinyl) 4,5 -tetrahydrobenzothiepine- 1,1-dioxide (89).
SUBSTITUTE SHEET (RULE 26) WO 97133882 PCTIUS97/04076 293 02
S
L~J'OH
89 A mixture of 0.20 g (0.49 mmol) of compound 78, and g (35 mmol) of aztidine was held at ref lux for 3 h and concentrated in vacuc. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO4. The ether solution was concentrated on a steam bath.
The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.S-199.5 0
C.
Example 49 (3zx,4r,5a) 3 -Butyl- 3-ethyl- 5- -methogyphenyl) -4hydroxy-7-methylthio-2, 3,4, 5-tetrahydrobnzothiepiie-1, 1dioxide (3cz,4j3,5J) 3-Butyl-3-ethyl-5-(3'maethoxyphenyl) -4-hydroxy-7 -zethylthio-2, 3,4, tetrahydrobenzothiepine-1, 1-dioxide (91).
02 02 S S
OH
CH3 Q OCH 3 91 A mixture of 0.4,g (0.95 mmnol) of compound 79, 0.08 g SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 294 (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 OC for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60 °C for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over MgSO, and concentrated in vacuo. The first fraction (0.1 g) was compound 90, mp 117- 121 OC. The second fraction (0.16 g) was compound 91, mp 68-76 OC.
Example Preparation of polyethyleneglycol functionalized benzothiepine A.
o O On
OCH
3 02 HO S so, 't H No. 136 No. 141 A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.055 g Compound No. 136, 0.326 CsCO 3 and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5 days and then the solution was SUBSTUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 295 filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC Si02) Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (Spectrum® 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present.
This material was active in the IBAT in vitro cell assay.
Example 51 Preparation of Compound 140 No. 140 SUBSITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 296 0 II y.iOH 0-7-
H
2 No. 111 A 2-necked 50 ml round bottom Flask was charged with 0.42g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG- Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, 0.100g of Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27 OC. TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water.
The organic layer was evaporated to dryness by means of a rotary evaporator. Dry wgt. 0-4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at oC through a cellulose dialysis tube (spectrum® 7 ,45mm x ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 NMR was consistent with the desired product B.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 297 Example 52
LI
No. 134 A 10 cc vial was charged with 0.21 g of Compound No.
136 (0.5mmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF.
The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No.
134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 298 Example 53 No.- 112 Example 54 aH 12 No. 113 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 299 A two necked 25 ml round bottom Flask was charged with 0.5g (1.24mmoles) of 69462, 13 mis of anhydrous DMF, 0.055g of 60% NaH dispersion and 0.230g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10 OC under nitogen. Next, the reaction was slowly heated to 40 OC. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water.
The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane).
Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.
Example S No. 135 Ira No. 136 In a 50 ml round bottom Flask, add 0.7g (1.8 mmoles) of SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 300 Compound No. 136, 0.621g of potassium carbonate, 6 ml DMF, and 0.33g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40 °C under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.
Examples 56 and 57 (Compound Nos. 131 and 137) The compositions of these compounds are shown in Table 3.
The same procedure as for Example 55 except appropriate benzothiepine was used.
Example 58 (Compound No. 139) The composition of this compound is shown in Table 3.
Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].
Example 59 (Compound No. 101) 61 H No. 101 This compound is prepared by condensing the 7-NH, benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 301 Example 60 (Compound No. 104) 0\
"OH
No. 104 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII.
Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIIUS97/04076 302 Scheme 6 0 Rl HJZ2 01's R 6
CHOH
NO,
XXIV
potassium t-butoxide,
THF
R 6 N'
H
H
XXIXC
SUBSWMUT SHEET (RULE 26) WO 97/33882 PCTIU~S97/04076 303 Example 61
N+
No. 102 A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50 °C for 4 days. The quat. Salt Compound No. 192 was isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.
Example 62 No. 125 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0 °C and then capped and warmed to room temperature. The reaction was stirred SUBSTTUTE SHEET (RULE 26) WO 97/33982 PCTIUS97/04076 304 overnight and the desired product was isolated by removing solvent by rotary evaporation.
Example 63 (Comipound No. 295) 00 I' 0-**a H2H
H
2 No. 113 Sodium Hydride 60% (11 mg, 0.27 inmoles) in 1 cc of acetonitrile at 0 'C was reacted with 0.248 nimoles (.10 g) of Compound No. 54 in 2.5cc of acetonitrile at 0 0 C. Next, 0O-(980g 2.48 nimoles) of 1, 2-Bis 2 -iodoethoxyl ethane].
After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 305 Example 64 (compound No. 286) PCT/US97I04076 PhCH 2 No. 286 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid; mp 180-181 0 C; I H NMR (CHCl 3 0. 85 J3 6 Hz, 0.92 J 6 Hz, 3H), 1.24-1.42 (mn, 2H), 1.46-1.56 (in, 1H), 1.64-1.80 (in, 1H), 2.24-2.38 (mn, 1H), 3.15 (AB, J AS 15 Hz, Av 42 Hz, 2H), 4.20 J 8 Hz, 1H), 5.13 2H), 5.53 1H), 6.46 1H), 6.68 1H), 7.29-7.51 (mn, 10H), 7.74 3 8 Hz, 1H), 8.06 J 8 Hz, 1H). FABMS m/z 494 HRMS calcd for 494.2001, found 494.1993. Anal. Calcd.
for C 2 8
H
3 1 NOS: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.
Example 65 (Compound No.--287) No. 287 Following a procedure similar to the one described in SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 306 Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 0 C, I NMR (CDCl 3 8 0.84 J 6 Hz, 0.92 J 6 Hz, 3H) 1. 28, J 8 Hz, 1H), 1. 32-1.42 (mn, 1H) 1. 48- 1. 60 (mn, 1H) 1. 64-1 .80 (mn, 1H) 2 .20-2.36 (mn, 1H) 3. 09 (AB, JM 15 Hz, Av 42 Hz, 2H), 3.97 (bs, 2H) 4.15 J 8 Hz, 1H) 5.49 1H) 5.95 1H), 6.54 J 7 Hz, 1H) 7.29-7.53 (mn, 5H) 7.88 J =8 Hz, 1H) ESMS 366 (M+Li) Anal. Calcd. for C 20
H
25 N03S: C, 66.82; H, 7. 01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.
Exainole- 66 (Comnound No. 288) H 24 No. 288 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186'C; 1 H NMR (CDC1 3 61. 12 3H) 1. 49 3H) 3. 00 J Hz, 1H1), 3. 28 J 15 Hz, 1Hi), 4. 00 1H) 5. 30 (s, 1H) 5.51 1H) 5.97 111), 6.56 (dd, J 2.1, 8.4 Hz, 1H) 7.31-7.52 (mn, 5H) 7.89 J 8.4 Hz, 1H) MS (FAB+) m/z 332.
Example 67 (Comp~ound No. 289) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 307 No. 289 Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206 "H NMR (CDC1,) 6 0.80-0.95 6H), 1.10-1.70 7H), 2.15 (m, 1H), 3.02 J 15.3 Hz, 2H), 3.15 J 15.1 Hz, 2H), 3.96 br, 2H), 4.14 J 7.8 Hz, 1H), 5.51 1H), 5.94 J 2.2, 1H), 6.54 (dd, J 8.5, 2.2 Hz, 1H), 7.28- 7.50 6H), 7.87 J 8.5 Hz, 1H). MS (FAB): m/z 388 Example 68 (Compound No. 290) No. 290 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 96-98 oC, 'H NMR (CDC1,) 8 0.92 J 7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 J 8 Hz, 1H), 3.09 (AB, J 18 Hz, Av 38 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 308 Hz, 2H), 3.96 (bs, 2H), 4.14 J 7 Hz, 1H), 5.51 (s, 111), 5 94 1H) 6.-5 6 J 9 Hz, 1H) 7. 4 1-7. 53 (in, 6H), 7. 87 J 8 Hz, 111); FARMS mn/z 416 Example 69 0 0 PhCH 2
O-.N
No. 291 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid: 'H NNR (CDCl,) 8 0. 91 i 7 Hz, 6H) 1. 02-1.52 (in, 11Hi), 1. 1.-7 0 (mn, 1H) 2. 23 J 8 Hz, 1Hi), 3 .12 (AB, JM 18 Hz, Av 36 Hz, 2H), 4.18 J =7 Hz, 1H), 5.13 2H), 5.53 1H) 6.43 1H) 6.65 1H) 7.29-7.52 (mn, 10H) 7.74 J 9 Hz, 1H) 8.03 J 8 Hz, 1H) ESMS m/z 556 (M+Li).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 309 Example 70 (Compound No.-292) No. 292 Following a procedure similar to the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 111- 112. 5 0 C, I H NMR (CDC1,) 8 0.90 J =8 Hz, 6H) 1.03-1.50 (mn, 10H) 1.55-1.70 (mn, 2H) 2.18 J 12 Hz, 2H) 3.07 (AB, JjW 15 Hz, Av =45 Hz, 2H) 4. 09 (bs, 2H) 5.49 (s, 1H) 5.91 1H) 6.55 J =9 Hz, 1H), 7.10 J 7 Hz, 2H-) 7.46 i 6 Hz, 2H), 7.87 J =9 Hz, 1H) SUBSTITUT SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 310 Example 71 (Comp~ound No. 293) 0 0 PhCH Na 2 0OH No. 293 During the preparation of Compound No. 290 from Compound No. 291 using M~r, the title compound was isolated: H NMR (CDCl 3 6 0. 85 J 6 Hz, 6i) 0.98-1.60 (mn, 10H), 1.50-1.66 (mn, 2H), 2.16 J 8 Hz, 1H), 3.04 (ME, J. 15 Hz, Av 41 Hz, 2H) 4.08 1H), 4.12 (s, 1Hi), 5.44 1H) 5.84 1H) 6.42 J =9 Hz, iH), 7.12 J 8 Hz, 2H) 7.16-7.26 (mn, 10H), 7.83 J 8 Hz, 1H); ESMS m/z 512 (M+Li).
Exampl-e-72 (Comn~ound No. 294) Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: 1H NMVR (CDCl 3 0.90 j =6 Hz, 6H) 1. 05-1.54 (mn, 9k), 1. 60-1.70 (mn, 1H) 2.24 1 8 Hz, iH), 2.80 6H), 3.05 (AB, Hz, Av 42 Hz, 2H), 4.05-4.18 (in, 2H), 5.53 1H), 5.93 1H) 6.94 J 9 Hz, 1H) 7.27-7.42 (mn, 4H) 7.45 (d, J 8 Hz, 2H) 7.87 J 9 Hz, 1H) ESI4S m/z 444 Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.
Examples 73-79, 87. 88 and 91-102 Using in each instance a method generally described in SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 311 those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and positions (R 3
R
4
R
5
R
6 and in the indicated position on the benzo ring Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.
Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]nitrobenzene.
In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mis chlorobenzene. Slowly add 60 gms acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.
In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq).
Chill solution with ice bath while purging with N2. Slowly add 40.3g aluminum chloride (1.2 eq 0.3 mole). Stir under N, for 24 hrs.
After 24 hrs, the solution was poured into 300 mls IN HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgS04, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57g (mixture of meta, ortho and para).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 312 Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 C1 12.15 12.16 With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.
4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.
Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.
Examples 85 and 86 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for 14 hours.
The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 313 the presence of 35 g of potassium carbonate and stirred at room temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.
The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at 0 C to yield compounds 117 and 118 which were separated by silica gel column chromatography.
Examples 89 and Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to. -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature. Reaction is complete after hours. The reaction is quenched by addition of potassium carbonate at 0 C and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.
Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 314 Table 3: Specific Compounds (#102-111, 113-130, 132-134, 136, 138, 142-144, 262-296) 0 0 10 (RX)q Cp# R1 R2
R
3 R5 (nX Ir 102 Et n-Bu- HO- 103 ri-Bu- Et- HO- Ph Ph Ph- Ph Ph 104 105 Et Et n-Bun-Bu-
HO-
HO-
106 Et- 107 n-Bu- 108 Et- 109 Etn-Bu- HO- H- Et- HO- H- p-n- Cl0H21--0-.
Ph n-Bu- HO- H- Phn-Bu- HO- H- p-n- C10H21--O- Phn-Bu- HO- H- Ph- Et- HO- H- p-HO-Phn-Bu- HO- H- p-HO-Phn-Bu- HO- H- p-CH3O-Ph- Et- HO- H- p-CH30-Ph- 7- (CH3) 3N+- 7- (CH3) 3N'- 7 (CH3 2N- 7- CH3 SO2NH- 7 -Br-CH2
CQNH-
7-NH2- 7- C5H1 1CONH- 7 -NH2 7-CH3CONH- 7 -NH2- 7 -NH2 7 -NH2 7 -NH-CBZ 110 ill 113 114 115 Etn-Bu- Et- Etn-Bu- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 315 Cp# 116 117 118 119 Etn-Bu- Et- Et n-Bu- Etn -Bu n-Bu-
R
3 HO HO
HO-
HO 120 n-Bu- EL- HO- H- 121 122 123 Et n-Bu- Et n -Bu Et-
HO-
HO n-Bu- HO- 124 n-Bu- EL- HO- H- 125 Et- n-Bu- HO- H-
R
p-CH3O-Ph- Ph- Ph Ph Ph Ph Ph Ph- Ph- Php -F Ph p-F-Php-F-Php-F -Ph- Ph- Ph- Ph- (RX) q 7 -NH-CBZ 7-NH-CBZ 7-NH-CBZ 7-NHCO2-t- Bu 7-NHCO2-t- Bu 7 -NH2 7 -NH2 7 -f-CH13
NH-
7 -n-COH13-
NH-
8- (CH3) 3) N+ CH2CH2O) 3- 7 -NH-CBZ 7-NH2- 7 -NH-CBZ 7 -NH2 8- (CH3)3N+ C6Hl20- 8-phthalimidyl- C6H120- 8-n- CjOH21- 126 127 128 129 130 n-Bun-Bu- Et- ELt- Et- Et- Etn-Bun-Bun-Bu- HO
HO-
HO-
HO-
HO-
132 EL- n-Bu- HO- H- 133 EL- n-Bu- HO- H- SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 316 Cp# 134 136 138 142 143 144 262 263 264 2-65 266 267 268 269 270 271 272 273 Et- Et n-Bu- Et- Et- Et- Et- Et- Et- Et- Et Et- Et- Et- Et- Et- Et- Et n-Bu n-Bu- Et n-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bu-
HO
HO HO
HO-
HO
HO-
HO
HO-
HO-
HO-
HO-
HO-
HO-
HO-
HO-
HO-
HO-
H-
H-
H-
H-
H-
HO-
H-
H-
HO-
HO-
HO-
H
H-
H-
HO-
HO-
H-
HO-
HO-
R
5 Ph Ph- Ph
H-
ml-CH3O-Php-F-Phxn-CH3O-Ph-
H-
m-CF3 -Ph-
H-
rn-HO-Phrn-HO-Php-F-Ph-
H-
p-F-Phrn-CH3O-Ph-
H-
H-
R
6 H
H-
H-
rn-CH3O-Ph-
H-
H-
H rn-CH3O-Ph-
H-
rn-CF3 -Ph-
H-
H-
H-
p -F -Ph
H-
H-
m-CH3O-Php-F-Ph- (RX)q 8- 1- (C2H 4 0) 3- 8- HO- 8- CH3CO2- 7-CH3S- 7-CH3S- 7- azetidine 7 -CH3O- 7 -CH3O- 7-CH3O- 7-CH3O- 7 -HO- 7 -CH3O- 7 -CH3O- 7-CH3O- 7 -HO- 7-Br- 7-Br- 7-F- 274 EL- n-Bu- HO- p-F-Ph- 7-F- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 317 Cp l
R
2
R
3
R
4
R
R6(RX)q9 275 Et- n-Bu- Hi- HO- H- M-CH3O--Ph- 276 277 278 279 280 281 282 283 284 Et- Et- Et- Et- Et- Et- Et- Et- Et n-Bun-Bun-Bufl-Bu fl-Bun-Bun-Bun-Bun-Bu-
HO-
HO-
H-
H-
HO-
HO-
HO-
H-
HO-
H-
H-
HO-
HO-
H-
H-
H-
HO-
H-
H-
H-
H-
H-
H-
H-
H-
m-C13 0-Phrn-F-Ph-
H-
H-
O -F -Ph p-F-Php-F-Ph-
H-
P-F-Php-F-Ph- Ph- Ph Ph Ph- Ph Ph-
H-
H-
o -F -Ph m -F -Ph
H-
H-
H-
p -F -Ph
H-
H-
H-
H-
H-
H-
H-
H-
7-F- 7-F- 7-CH30- 7-CH3O- 7-CH3O- 7 -CH 3
O-
7-CH3S- 7-CH3- 7-CH3- 7- morpholine 7- pyrroli- Idine 7-NH-CBZ- 7 -NH2 7 -NH2 7 -NH2 7-NH2- 285 EL- n-Bu-
HO-
286 287 288 289 290 291 Et Et- CH3 C3H7n-Bufl-Bu-
EL-
Et- CH3 C3H7n-Bun-Bu-
HO-
HO-
HO-
HO-
HO-
HO-
292 n-Bu- n-Bu- HO-
H-
p-F-Ph- 7 -NH2 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 318 Cp# R1 R 2
R
3
R
4 293 n-EBu- n-Bu- HO- H- 294 n-Bu- n-Bu- HO- H- 295 Et- n-Eu- HO- H-
R
Ph Ph p-I (C2H40) 3- Ph (RX) q 7-PhCH2N- 7 (CJ-3 2N- 7 -NH2 296 Et- n-Eu- HO- Hp- (CH3) 3N+ (C 2H40) 3-Ph- 7 -NH2- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 319 TABLE 3A Bridged Benzothiepines (#101, 112, 131, 135, 137, 139-141) HN
N-
0 0~ CPD 101 (Example 59)
NH,
H.,N
CPD #112 (Example 53) CPD #131 (Example 56) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 320 CPD 135 (Example CPD 137 (Example 57) CPD 139 (Example 58) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT1US97/04076 321
PEG
NH-, HN PEG 3400 molecular weight polyethyleneglycol bridge CPD 140 (Example 5 1) CPD #141 (Example SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 322 Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R 3
R
4 R R 6 and in the indicated position on the benzo ring SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 323 Table 4: Alternative compounds #1 (#302-312, 314-430) 0 0 'i Et n-Bu (Rx) q
OH
CPd# 302 303 304 305 306 307 308 309 310 311 312 314 315 316 317 318 319 p- F -Ph p -F -Php -F -Ph p -F -Php-F-Php-F-Php -F -Php-F-Php -F -Php-F-Ph-
-H
3 -Ph m-Ci 3 O-Phm-CH 3 0-Phm-CH 3 O- Phm-CH 3 O-Phm-CH 3 0-Phq 7- (1-aziridine) 7-EtS- 7-CH 3 S(0) 7-CH 3 S 2 7-PhS- 7-CH 3
S-
9-CH 3
S-
7 -CH 3
O-
9-CH 3
O-
7-Et- 7-i Pr 7- t-Bu 7-U(-pyrazole) 7- (1-azetidine) 7- (1-aziridine) 7-EtS- 7-CH 3 S 7-CH 3 S 2 7-PhS- SUBSTITTE SHEET (RULE 26) WO 97/33882 PTU9147 PCT/US97/04076 324 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 m-CH 3 O-Ph
M-CI{
3 0-Ph m-CH 3 O-Ph rn-CH 3 O-Ph in-CH 3 O-Ph p -F -Ph p -F -Ph p -F -Ph p-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php -F -Ph 7-CH 3
S-
9-CH 3
S-
7 -CH 3
O-
9-CH 3
O-
7-Et- 7-iPr- 7-t-Bu- 6-CH 3
O-
7-CH 3
O-
8-CH 3
O-
7- (1-azetidine) 9-CH 3 7-EtS- 9-CH 3 7-CH 3 S 9-CH 3 7-CH 3 S 2 9-CH- 3 7-PhS- 9-CH 3 7-CH 3
S-
9-CH 3 7-CH 3
O-
9-CH 3 7 -CH 3 9 -CH 3 7-CH 3
O-
9 -CH 3
Q-
7- (1-pyrrole) 7- N'-methylpiperazine Ph- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PTU9147 PCTfUS97/04076 325 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 p -F -Ph p -F -Ph p -F -Ph p -F -Ph p -F -Ph p -F -Ph rn-CH- 3 0-Phrn-CH 3 O-Phrn-CH 3 0-Phrn-CH 3 -Phin-CH 3 O-Phrn-CH 3 -Phrn-CH 3 O-Phin-CH 3 O--Phin-CH 3 O-Phrn-CH 3 -Phm-CH 3 O-Phrn-CH 3 O-Phrn-CH- 3 0-Ph- 7 -CH 3 C (=CH 2 7-cycipropyl 7- (CH 3 2
NHN-
7- -azetidine 9-CH 3
S-
7- (N-pyrrolidine) 9-CH 3
S-
7- (CH 3 2
N-
9-CH 3
S-
7- (1-pyrazole) 7- N' -iethylpiperazine Ph 7 -CH 3 C (=CH 2 7 -cyclopropyl 7 (CH 3 2
NHN-
7- -azetidine 9-CH 3
S-
7 (N-pyrrolidine) 9-CH 3
S-
7-(CH 3 2
N-
9-CH 3
S-
6 -CH 3
O-
7 -CH 3
O-
8-CH 3
Q-
7- (1-azetidine) 9-CH 3 7-EtS- 9-CH 3 7-CHi 3 S 9-CH 3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 326 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 m-CH 3 O-Ph-
'-CH
3 O-Phm-CH 3 O-Phm-CH 3 O-Phn- CH 3 0-Ph m-CH 3 O-Phthien-2-yl thien-2 -yl thien-2-yl thien-2 -yl thien-2-yl thien-2 -yl thien-2-yl thien-2 -yl thien-2 -yl thien-2-yl thien-2 -yl thien-2 -yl thien-2-yl thien-2 -yl thien-2-yl 7-CH 3 S 2 9-CH3- 7-PhS- 9 -CH 3 7-CH 3
S-
9 -CH 3 7-CH 3
O-
9-CH 3 7-CH 3 9 -CH3 7-CH 3 0- 9-CH 3
O-
7- (1-aziridine) 7-EtS- 7-CH 3 S 7-CH 3 S 2 7-PhS- 7-CH 3
S-
9-CH 3
S-
7-CH 3
O-
9 -CH 3
O-
7-Et- 7-iPr- 7- t-Bu- 7- (1-pyrrole) 7-CH 3 0- 7-CH 3
S-
7- (1-azetidine) 7-Me- SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT1US97/04076 327 378 379 380 381 382 383 384 385 386 387 388 389 390 3 9 392 393 394 395 396 397 398 5-Cl-thien-2-yl 5-C1-thien-2-y.
5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-C1-thien-2-y.
5-Cl-thien-2-yl 5-Cl-thien-2 -yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2 -yl 5-C1-thien-2-yl 5 -C1-thien-2 -yl 5-Cl-thien-2-yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl 7- (1-azetidine) 7- (1-aziridine) 7-EtS- 7-CH 3 S 7-CH 3 S 2 7- PhS 7-CI1 3
S-
9-CH 3
S-
7 -CH 3
O-
9-CH 3 0- 7-Et- 7-iPr- 7- t 7 -CH 3
O-
7-CH 3
S-
7-Me 7- (1-azetidine) 9-CH 3 7-EtS- 9 -CH 3 7-CH 3 S 9-CH 3 7-CH 3 S 2 9-CH 3 7-Phs- 9-CH4 3 7-CH 3
S-
9-CH 3 7-CH 3
O-
9 -CH 3 SUBSTITE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 328 399 400 401 402 403 404 405 406 407 408 409 411 412 413 414 415 416 417 418 419 thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2-yl thien-2 -yl thien-2 -yl thien-2-yl 5-C-thien-2-yl 5-C-thien-2-yl 5-C-thien-2-yl 5-C1-thien-2 -yl 5-C1-thien-2 -yl 5-Cl-thien-2-yl 5-C-thien-2-yl 5-C1-thien-2-yl 5-C-thien-2-yl 7 -CH 3 9-CH 3 7 -CH 3
O-
9-CH- 3 0- 7- (1-pyrazrole) 7- N' -iethylpiperazine Ph 7 -CH- 3 C (=CH 2 7 cyc lpropyl 7-(CH 3 2
NHN-
7- -azetidine 9-CH 3
S-
7- (N-pyrrolidine) 9-CH 3
S-
7-(CH 3 2
N-
9-CH 3
S-
7- (1-pyrazrole) 7- -methylpiperazine Ph- 7 -CH 3 C (=CH 2 7 -cyclopropyl 7 -(CH 3 2
NHN-
7- -azetidine 9-CH 3
S-
7 (N-pyrrolidine) 9-CH 3
S-
7-(CH 3 2
N-
9-CH 3
S-
SUBS11TUTE SHEET (RULE 26) WO 97133882 WO 9733882PCTIUS97/04076 329 420 421 422 423 424 425 426 427 428 429 430 5-C1-thien--2-yl 5-C-thien-2-yl 5-Cl-thien-2-yJ.
5-C-thien-2-yl 5-C-thien-2-yl 5 -C1-thien-2-yl S-C1-thien-2-y- 5-Cl-thien-2--yl 5-C-thien-2-yl thien-2-yl 5-C1-thien-2 -yl 7- (1-azetidine) 9-CN 3 7-EtS- 9-CH 3 7 -CH 3 S 9-CH 3 7-CH 3 S (0)2- 9-CH 3 7-PhS- 9-CH 3 7-CH 3
S-
9-CH 3 7-CH 3
O-
9-CH 3 7 -CH 3 9 -CH 3 7-CH 3 0- 9-CH 3
O-
6-CH 3 0- 7-CH 3
O-
8-CH 3
O-
6-CH 3 0- 7-CH 3 0- 8-CH 3
O-
SUBSTITUE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 330 Examples 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R 2
R',
and in the indicated position on the benzo ring Example 1395 Dibutyl 4-fluorobenzene dialdehyde 0 s0 Bu F 4
OH
C
Br Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde To a stirred solution of 17.5 g (123 mmol) of difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO,) and SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 331 concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g of fluorobenzene dialdehyde as a yellow oil: 1 H NMR (CDC13) d 0.87 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.5-1.78 (m, 4H), 3.09 2H), 7.2-7.35 1H), 7.5-7.6 2H), 9.43 1H), 10.50 J 2.62 Hz, 1H).
Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HC1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO,), and concentrated in vacuo.
Silica gel chromatographic purification of the crude product gave 13.5 g of recovered starting material, and 8.1 g of the desired fluorobenzyl alcohol as a colorless oil: 1 H NMR (CDC13) d 0.88 J 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 4H), 1.94 (br s, 1H), 3.03 2H), 4.79 2H), 6.96 (dt, J 8.46, 3.02 Hz, 1H), 7.20 (dd, J 9.47, 2.82 Hz, 1H), 7.42 (dd, J 8.67, 5.64, 1H), 9.40 (s, 1H).
Step 3: Preparation of dibutyl 4-fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich).
The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgS04), and concentrated in vacuo. The mixture was stirred in small SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS9/04076 332 amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g of the desired product as a colorless oil: 1 H NMR (CDC13) d 0.88 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.55-1.78 4H) 3.11 2H), 4.67 (s, 2H), 7.02 (dt, J 8.46, 3.02 Hz, 1H) 7.15 (dd, J 9.47, 2.82 Hz, 1H), 7.46 (dd, J 8.67, 5.64, 1H), 9.45 1H).
Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CHC1, at 0 OC was added 15.9 g mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na 2 CO,, dried (MgSOand concentrated in vacuo to give 10.2 g of the desired product as a colorless oil: 1H NMR (CDC13) d 0.91 J 7.05 Hz, 6H), 1.03-1.4 8H), 1.65-1.82 2H), 1.90-2.05 2H), 3.54 2H), 5.01 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J 8.87, 2.42 Hz, 1H), 8.03 (dd, J 8.86, 5.64, 1H), 9.49 1H).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTUS97/04076 333 Generic Scheme X
RX
CHO
1. Li 2 S, DMSO, heat 2. mesylate aldehyde, heat
R
Rx CHO
CHO
1. butyl lithium PMETA, deg C, THF 2. DMF Rx R1 S R-R Rx
CHO
Br PMETA
I
BrPhIPBr, -40 deg C
DMF
DIBAL, THF, deg C R
I
CHO
OH
MCPBA m-chloroperbenzoic acid
MCPBA
0, ,R
CHO
Br
R'B(OR)
2 heat Pd(Ph 3
P)
4 Na 2
CO
3 Ethanol, toluene, or DMIE or
R
5 SnR 3 heat Pd(Ph 3
P)
4 solvent R H, or CI-C 6 alkyl 02
R
Rx-
CHO
R
base potassium t-butoxide) 02
R
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 334 Example 1396 0
S
N o H S 0 OH Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO etc), followed by the addition of dialkyl mesylate aldehyde provided a dialkyl benzene dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z.
Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate
W.
Preparation of N-propylsulfonic acid To a solution of 51 mg (111 pm) Compound X in ethanol (400 ul) was added 1,3 propane sultone (19.5 1l, 222 un).
The reaction was stirred in a sealed vial at 55 oC for hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 'H NMR (CDCL,) d 0.82-0.96 6H), 1.11-1.52 (m of m, SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97104076 335 1.58-1.72 (mn, 1H) 2.08-2.21 (mn, 1h) 2.36-2.50 (mn, 2H), 2.93 6H), 3.02-3.22 (inof mn, 5H), 3.58-3.76 (mn, 2H), 4.15 1H), 5.51 1H), 6.45-6.58 (mn, 1Hi), 6.92-7.02 (mn, 1H), 7.35-7.41 (mn, 1H), 7.41-7.51 (mn, 2H), 8.08 J 8.1 Hz, 1H) 8.12-8.25 (mn, 1H) MS ES- M-H m/z 579.
Example 1397 The 7-f luoro, 9-f luoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.
3, 3-Dibutyl-5a- (41 -f luorophenyl) -4a-hydroxy-7methylthio- 2, 3,4, 5 -tetrahydrobenzothiLepile- 1. ,1-dioxide.
0 0 Bu l Bu MeS
OH
F
A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4fluorophenyl) -4a-hydroxy-2, 3,4, 1, 1-dioxide, prepared by previously described method, 0 .12 g of sodium iethanethiolate and 20 ml of DMF was stirred at C for 3 days. An additional 0.1 g of sodium iethanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C then was concentrated in vacuo. The residue was triturated with water and extracte SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 336 wiith ether. The ether extract was dried over MgSO 4 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164- 165.5 %C.
3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide and 7,9-Bis (dimethylamino) -3,3-dibutyl-5a-(4'fluorophenyl) -4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide.
Me 2 N O Me 2 N 0 O S BU \Bu 11 Bu F Bu Me 2
N
F O OH
OH
FF
F
A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-5a- (4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgSO 4 and concentrated in vacuo. The resdue was purified by HPLC EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a- (4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-l,1-dioxide, MS (CI) m/e 480 (M and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4 '-fluorophenyl)-4a- SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 337 hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505 (M The compounds of this invention can also be synthesized using cyclic sulfate below) as the reagent as shown in the following scheme. The following example describes a procedure for using the cyclic sulfate as the reagent.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 973388ZPCTIUS97/04076 338 R, R 2 OH OH SOC1 2 RuC13, NaIO 4 R, 2 0 0 I .NaH, diglyme 2 HO/ PCC. CHI 2
CI
2 2.
(RY)P
0 0 3. H-)S0 4 R2 MCPBA (RX) I (Ry)p K~tBu (Fty) (Ry)p SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 339 Dibutyl cyclic sulfite: 0 A solution of 2,2-dibutyl-l,3-propandiol (103g, 0.548 mol) and triethylamine (221g, 2.19 mol) in anhydrous methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) was consistent with the product.
To a solution of the above compound (127.5g 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left.
The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite.
The filtrate was concentrated under vacuum and gave .the SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 340 cyclic sulfate 133 g as an oil. Proton, carbon NMR and MS were consistent with the product.
-Fluorobenzyl) -4-methylphenylthio)methyl] -2butylhexanol:
S
H
3 C' -OH
F
Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmole), was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2methoxyethyl ether (diglyme) and the mixture was cooled in an ice bath. A solution of 1.55-g (6.68 mmole) of fluorobenzyl)-4-methylbenzenethiol" in 10 ml of 2methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2-methoxyethyl ether was added once and stirred for 30 min at 0 C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HC1 and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated under vacuum to give 2.47 g SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 92.5%) of an oil. Proton NMR consistent with the product.
13C NMR and MS were 2-[(2-(4'-Fluorobenzyl)-4-methylphenylthio)methyl]-2butylhexanal: To a solution of the above product (2 g 4.9 mmol) in ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel. The filtrate was concentrated under vacuum to give 1.39 g of an oil.
Proton, carbon NMR and MS were consistent with the product.
2-[(2-(4'-Fluorobenzyl)-4-methylphenylsulfonyl)methyl]- 2-butylhexanal To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% m-chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 342 18 hrs and filtered. The filtrate was washed successively with 10% NaOH water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g of an oil. Proton, carbon NMR and MS were consistent with the product.
3,3-Dibutyl-7-methyl-5a-(4'-fluorophenyl)-4a-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide: O1
S
-H3C
'COH
F
A mixture of 0.37 g (0.85 mmol) of the above product in ml of anhydrous THF was stirred at 0 Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HC1 and extracted with ether. The ether extract was washed successively with water and brine, dried with MgSO 4 and concentrated under vacuum. The residue was purified by HPLC EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white solid, 0.27 g Proton NMR and carbon NMR were consistent with the desired product. Mass spectrum (CI) also confirmed the product, m/e 433 (M 1).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 343 Example 1398 Step 1 Cl O C]/o/CH3 NO2 CA HIC1NO, fw=291.69 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml round bottom flask. Fit flask with a N, inlet adapter and suba seal. Remove from inert atmosphere and begin N, purge. Add 50mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1, via syringe and begin stirring with magnetic stir bar.
Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N, purge. Stir at room temperature overnight. After stirring at room temperature for place in oil bath and heat at 50C for lhr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere.
In inert atmosphere, dissolve acid chloride with 105mls anhydrous anisole (0.97 mole Aldrich 29,629-5).
Place solution in a 2-necked 500ml round bottom flask.
Weigh out 45.1gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel. Fit reaction flask with addition funnel and a N 2 inlet adapter.
Remove from inert atmosphere. Chill reaction solution with ice bath and begin N, purge. Slowly add AlCl, to chilled solution. After addition is complete, allow to warm to room SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 344 temperature. Stir overnight Quench reaction by pouring into a solution of 300 mis IN HC1 and ice. Stir 15 min. Extract twice with ether.
Combine organic layers and extract twice with 2% NaOH, then twice with deionized HO. Dry with MgSO filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%. Obtain NMR and mass spec (m/z=292).
Step 2 Cl 0 O/CH3 NO2
C
1 4
H
12 C1NO, fw=277.71 Dissolve 38.10gms (0.131 moles) of the benzophenone from step 1 in 250mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N, inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.
Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mis anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N 2 Stir 5 minutes after addition is complete.
Prepare a solution of 22.85 gms triethyl silane (0.197mole Aldrich.23,019-7) and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Stir 5 minutes after addition is complete.
Prepare a second solution of 39.32 gms trifluoromethane SUBSTUTE SHEET (RULE 26 WO 97/33882 PCT/US97/04076 345 sulfonic acid and 170mls anhydrous methylene chloride.
Place in addition funnel and add dropwise to chilled solution under N 2 Stir 5 minutes after addition is complete.
Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under After all additions are made allow to slowly warm to room temperature overnight. Stir under N, overnight.
Prepare 1300 mls saturated NaHCO, in a 4 liter beaker.
Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min.
Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride. Dry organic layers with MgSO,.
Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278).
Step 3 0
H
S
0 CH3 NO2
C
25
H
3 HNO4S fw=443.61 Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N, inlet, and stopper. Add 1.84 gms Li,S (0.040 moles Aldrich SUBSTITE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 346 21,324-1). Place flask in oil bath and heat at 75 0 C under N, overnight then cool to room temperature.
Weigh out 10.59 gms dibutyl mesylate (0.040 moles).
Dissolve with anhydrous DMSO and add to reaction solution.
Purge well with heat overnight at 80 0
C.
Cool to room temperature. Prepare 500 mis of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times.
Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).
Step 4 0
H
0 s o^-,CH3 0 NO2
C
25
H
33 NOS fw=475.61 Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill solution with ice bath under N, purge. Slowly add 11.54 gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, After addition is complete warm SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 347 to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% KCO),. Extract aqueous layer twice with methylene choride. Combine organic layers and dry with MgSO,. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).
Step 0
H
OS
O/CH3 H3C N\H3
C
27 H39NOS fw=473.68 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mis ethanol. For safety reasons next two compounds are added in a N, atmosphere glove bag. In glove bag, add 15.3 mis formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H,.
Heat to 55°C under Run reaction at 200 psig and a stir rate of 250 rpm. Run overnight under these conditions.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 348 Cool reactor and vent H 2 Purge with Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether. Rotovap and redissolve with ether. Extract with water. Dry organic layer with MgSO4, filter and rotovap to dryness. Dry on vacuum line.
Charge reactor again with same amounts, seal reactor and run overnight under same conditions. After second run all of the material has been converted to the desired product. Cool and vent H 2 pressure. Purge with N 2 Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO filter and rotovap to dryness.
Dry on vacuum line. Obtain NMR and mass spec (m/z=474).
Step 6 0 OHCH3
N
H
3 C
CH
3
C
2
,H
39
NO
4 S fw=473.68 Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N 2 inlet and stopper.
Chill solution with ice/salt bath under N, purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 349 monitoring by TLC. Once reaction is complete, quench by adding 135 mis 10% HC1 stirring 10 min. Extract three times with ether. Dry organic layer with MgSO 4 filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).
Step 7 S '""OH S^
OH
N
H
3 C CH 3
C
2
H,,
3 NOS fw=459.65 Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mis anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a N, purge. Slowly add, via syringe, 2.84 mis boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature. Monitor reaction progress by TLC.
Reaction is usually complete in 3 hrs.
Chill solution with ice bath. Quench with 100 mis
K
2 CO, while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer.
Extract organic layer once with 10% HC1, once H,0, and once with saturated NaCl solution. Dry organic layer with MgSO 4 filter and rotovap to dryness. Crystallize product from SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 350 ether. Obtain NMR and mass spec (m/z=460).
Step 8 S\ r"""OH O
N
H
3 C CH 3
C
32
H
4 NOSI fw=701.71 Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper.
Chill NaH with ice bath and begin N, purge.
Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms KCO, (9.57 mmoles Fisher P-208).
Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mis anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40'C overnight under N 2 Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H 2 0, and saturated NaC1. Dry organic layer with MgSO 4 filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 351 Step 9 s
'H
NN+
N
H
3 C C H 3
C
3
H
63 N,SI fw=802.90 Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mis anhydrous acetonitrile. Purge well with N 2 then close system Heat at 45'C. Monitor reaction by TLC.
Reaction is usually complete in 48 hrs.
Perform cleanup by removing acetonitrile under vacuum.
Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether. Repeat several times.
Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 352 Example 1399 Step 1. Preparation of 1 Br C .IOCH3 To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel. Stirred at ambient temperature for fifteen minutes. Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO, and concentrated in vacuo. Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g of 1 as a clear colorless liquid. 1H NMR (CDC1 3 d 3.39 3H), 4.42 2H), 7.18-7.27 2H), 7.12 J 7.45, 1H), 7.50 1H).
Step 2. Preparation of 2
FFO
OCH
3 To a cooled (-78 solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol) The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C, cooled to -10 oC and to it was added 6 g of Pd(PPh,) 4 (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 quenched with water, SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 353 partitioned between ethyl acetate and water, and washed organic layer with IN HCL and with IN NaOH. The organic layer was dried over MgSO 4 and concentrated in vacuo.
Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43 of 2 as an orange oil. 'H NMR (CDC1 3 d 3.40 3H), 4.51 2H), 7.12-7.26 3H), 7.47 J 7.50, 1H), 7.57 (d, J 7.45, 1H), 7.73 J 7.45, 1H), 7.80 1H).
Step 3. Preparation of 3 B U
OH
,,OCH 3 A solution of 53 g (202.3 nmmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 CC) and 60.7 g of X' (the cyclic sulfate compound of example 1397) (242.8 mmol) in mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo. Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO 4 and condensed in vacuo.
Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate hexanes as elutant gave 42.9 g (48 of 3 as a yellow oil. 1H NMR (CDC 3 d 0.86 J 7.25 Hz, 6H); 1.10 1.26 12H), 2.83 2H), 3.32 2H), 3.40 3H), 4.48 3H), 7.02 (dd, J 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J 8.19 Hz and 2.82 Hz, 1H), 7.45 J 7.65 Hz, 1H), 7.56-7.61 2H), 7.69 J 7.85 Hz, 1H), 7.74 1H).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 354 Step 4. Preparation of 4 o-$Bu r, Bu F l
CH
2
OH
1N OCH 3 To a cooled (-40 solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol) Stirred at -20 °C for two hours, quenched with water and warmed to ambient temperature. Partitioned between methylene chloride and water, dried the organic layer over MgSO 4 and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4 as a oil. 'H NMR (CDC1,) d 0.89 J 7.05 Hz, 611H), 1.17 1.40 12H), 1.46 J 5.84 Hz, 1H), 2.81 2H), 3.38 3H), 3.43 J 5.23 Hz, 2H), 4.16 2H), 4.42 2H), 6.80 J 9.67 Hz, 1H), 6.90 J 8.46 Hz, 1H), 7.09 J 7.45 Hz, 1H), 7.15 7.21 2H), 7.25- 7.32 2H), 7.42 (m, 1H).
Step 5. Preparation of Y Bu
CHO
'.,OCH 3 To a cooled (15-18 solution of 24.2 g (55.8 rmmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 355 (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed in vacuo to give 23.1 g (96 of 5 as a light brown oil. -H NMR (CDCl 3 d 0.87 J 7.05 Hz, 6H), 1.01 1.32 8H), 1.53 1.65 4H), 2.98 2H), 3.38 3H), 4.15 2H), 4.43 2H), 6.81 (dd, J 9.66 Hz and 2.82 Hz, 1H), 6.91 J 8.62 Hz, 1H), 7.07 J 7.46 Hz, 1H), 7.14 1H), 7.19 J 7.65 Hz, 1H), 7.26 7.32 1H), 7.42 (dd, J 8.66 Hz and 5.64 Hz, 1H), 9.40 1H).
Step 6. Preparation of 6 0 S Bu pA~k
CHO
,,OCH 3 To a cooled (0 solution of 23.1 g (53.6 mmol) of in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 nmmnol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na 2
SO
3 partitioned between water and methylene chloride. Dried organic layer over MgSO 4 and condensed in vacuo to give 24.5 g of 6 as a light yellow oil. 1H NMR (CDCl 3 d 0.86 1.29 14H), 1.58 1.63 2H), 1.82- 1.91 2H), 3.13 2H), 3.39 3H), 4.44 2H), 4.50 2H), 6.93 J 9.07 Hz, 1H), 7.10 7.33 5H), 8.05 1H), 9.38 1H).
SUBSTIT UTE SHEff (RUU 26) WO 97/33882 PCT/US97/04076 356 Step 7. Preparartion of 7 .Ie f-\SBu Me 2N
C
HO
MegN ,OCHa To a solution of 24.5 g (52.9 nmmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 'C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo.
Purification by silica gel chromatography (Waters Prep-500) using 15 ethyl acetate/hexanes gave 21.8 g (84 of 7 as a clear colorless oil. 'H NMR (CDCl,) d 0.85 J 7.25 Hz, 6H), 0.93 1.29 8H), 1.49 1.59 2H), 1.70 1.80 2H), 2.98 8H), 3.37 3H), 4.41 2H), 4.44 (s, 2H), 6.42 1H), 6.58 (dd, J 9.0 Hz and 2.61 Hz, 1H), 7.13 J 7.45-Hz, 1H), 7.21 1H), 7.28 J 7.85 Hz, 1H), 7.82 J 9.06 Hz, 1H), 9.36 1H).
Step 8. Preparation of 8
S
a "'OCH3 A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride. The organic layer was SUBSITE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 357 partitioned between ethyl acetate and water, dried over MgS04 and concentrated in vacuo. Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi') m/e 494.6. HRMS calculated for M+H 487.2756. Found 487.2746.
Step 9. Preparation of 9 0 Me 2N r Bu
OH
QQBr A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10 °C and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO 4 and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g of 9 as a white solid. MS (FABH') m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.
Step 10. Preparation of ,Bu MegN O -IB
SOH
Br" A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 358 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/ diethyl ether gave 1.19 g of 10 as an off white solid. MS (FAB') m/e 535.5.
Example 1398 Step 1. Preparation of 2 00 S Bu
CHO
NO
2 To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8.g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO 4 and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g of the title compound as a yellow solid. "H NMR (CDC1 3 d 0.88 J 7.45 Hz, 6H), 0.99-1.38 8H), 1.62-1.75 2H), 1.85-2.00 2H), 3.20 2H), 4.59 (s, 2H), 6.93 (dd, J 10.5 and 2.4 Hz, 1H), 7.15 (dt, J 8.4 and 2.85 Hz, 1H), 7.46-7.59 2H), 8.05-8.16 3H), 9.40 1H).
Step 3. Preparation of 3 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 359 0 I ,Bu
SOH
OI1NO N02 A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0 "C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 OC. Stirring was continued for minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CHC1, as eluent yielded 4.3 g of 3 as a pale yellow foam. 'H NMR (CDC1 3 d 0.93 J 7.25 Hz, 6H), 1.00-1.55 8H), 1.59-1.74 3H), 2.15-2.95 (m, 1H), 3.16 (qAB, JAB 15.0 Hz, AV 33.2 Hz, 2H), 4.17 J 6.0 Hz, 1H), 5.67 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J 8.5 and 2.9 Hz, 1H), 7.64 J 8.1 Hz, 1H), 7.81 J 8.7 Hz, 1H), 8.13 (dd, J 9.9 and 3.6 Hz, 1H), 8.23-8.30 1H), 8.44 1H). MS(FABH m/e (relative intensity) 464.5 (100), 446.6 HRMS calculated for M+H 464.1907. Found 464.1905.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 360 Step 4. Preparation of 4 0 o
,B
fH'
BU
M e 2 N Bu 1 OH (aN02 To a cooled (0 solution of 4.3 g (9.3 mmol) of 3 in ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g of 4 as a yellow solid. 'H NMR (CDC1 3 d 0.80-0.95 (m, 6H), 0.96-1.53 8H), 1.60-1.69 3H), 2.11-2.28 (m, 1H), 2.79 6H), 3.09 (qAB, JAB 15.0 Hz, DV= 45.6 Hz, 2H), 4.90 J 9.0 Hz, 1H), 5.65 1H), 5.75 J 2.1 Hz, 1H), 6.52 (dd, J 9.6 and 2.7 Hz, 1H), 7.59 J 8.4 Hz, 1H), 7.85 J 7.80 Hz, 1H), 7.89 J 9.0 Hz, 1H) 8.20 (dd, J 8.4 and 1.2 Hz, 1H), 8.43 1H).
MS(FABH m/e (relative intensity) 489.6 (100), 471.5 HRMS calculated for M+H 489.2423. Found 489.2456.
SUBSITUTE G IET (RULE 26) WO 97/33882 PCTI/US97/04076 361 Step 5. Preparation of 0 a. B MgBu Me 2 N 'OH NH2 To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g palladium on carbon. The reaction vessel was sealed, purged twice with then charged with H, (100 psi) and heated to 45 °C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g of 5. 'H NMR (CDC1,) d 0.80-0.98 6H), 1.00- 1.52 10H), 1.52-1.69 1H), 2.15-2.29 1H), 2.83 6H), 3.07 (qA, JAB 15.1 Hz, DV 44.2 Hz, 2H), 3.70 2H), 4.14 1H), 5.43 1H), 6.09 J 2.4 Hz, 1H), 6.52 (dd, J 12.2 and 2.6 Hz, 1H), 6.65 (dd, J 7.8 and 1.8 Hz, 1H), 6.83 1H), 6.93 J 7.50 Hz, 1H), 7.19 J 7.6 Hz, 1H), 7.89 J 8.9 Hz, 1H).
MS(FABH m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670.
Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6 mmol) TEA. The reaction was stirred minutes, then partitioned between ethyl acetate and brine.
The organic layer was dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 362 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g of 6 as a pale yellow oil. 1H NMR (CDCl 3 d 0.84-0.95 (in, 6H) 1.02-1.53 (mn, 10H), 1.53-1.68 (mn, 1H), 1.80-2.00 (mn, 2.12-2.26 (mn, 4H), 2.38 J 6.9 Hz, 2H), 2.80 6H), 3.07 (qAB, JAB 15.6 Hz, DV 40.4 Hz, 2H), 3.43 J =6.9 Hz, 2H), 4.10 1H), 5.51 1H), 5.95 J 2.4 Hz, 1H), 6.51 (dd, J =9.3 and 2.7 Hz, 1H), 7.28 1H), 7.32-7.41 (mn, 2H), 7.78 J 8.1 Hz, 1H), 7.90 J =9.0 Hz, 1H).
Step 7. Preparation of 7 C 1B0 Bu Me 2 N)
"OH
N)K,-,-,NEt 3
TFA
H
To a solution of 0.9g9 (1.45 rrimol) of 6 in 25 ml acetonitrile add 18 g (178 minol) TEA. Heat at 55 C-C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile) gave 0.8 g of 7 as a white foam. "H NMR (CDCl 3 d 0. 80-0.96 (mn, 6H) 0. 99-1.54 (mn, 19H), 1.59-1.84 (mn, 3H), 2.09-2.24 (mn, 1H), 2.45-2.58 (in, 2H), 2.81 6H), 3.09 (qAB, JAB 15.6 Hz, DV 18.5 Hz, 2H) 3.13-3.31 (mn, 8H) 4.16 1H) 5.44 1H) 6.08 (d, J 1. 8 Hz, 1H) 6. 57 (dd, J 3 and 2. 7 H z, 1H), 7.2 4 (t, J 7.5 Hz, 1H), 7.34 J =8.4 Hz, l1H), 7.56 J 8.4 Hz, 1H) 7.74 1H) 7.88 J 9.0 Hz, 1H), 9.22 (s, SUBS TE SHEET (RULE26 WO 97/33882 PCT/US97/04076 363 1H). HRMS calcd 642.4304; observed 642.4343.
Example 1400 Step 1
OH
OMe
F
C
1 4
H
1 3 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N 2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.
After 15 h. refluxing, the mixture was cooled to room temperature and poured into H 2 0 (2.5 After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min.
The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq.
KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried (MgSO 4 filtered and concentrated in vacuo. The crude product was purified by Kugelrohr SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 364 distillation to give a clear, colorless oil (449.0g/39% yield), 120-130 C/50mtorrHg. 1H NMR and MS H)4 233] confirmed desired structure.
Step 2
C
17
H
18
NO
2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/1.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H 2 0 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H 2 0 and saturated aqueous NaCI, dried (MgS0 4 filtered, and concentrated in vacuo to give the product 6 05.3g, 97% yield).
desired structure.
1H NMR and MS 320] confirm SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIIS97/04076 365 Step 3
SH
OMe
F
C
14
H
13 0FS fw=248.32 A 12-liter, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with H 2 0.
The aqueous extracts were combined, acidified with concentrated HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1H NMR confirmed desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 366 Step 4
HO
OMe
F
C
2 5
H
3 5 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and concentrated H 2
SO
4 was added.
The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO 4 filtered, and conc'd in vacuo to give an amber oil (143.94g/85% yield). 1 H NMR and MS H) 419] confirm the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 367 Step r0 SBu Bu OMe
F
C
2 5
H
3 3 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, and mechanical stirrer. The system was purged with N 2 The corresponding alcohol (143.94g/343.8mmol) and CH 2 Cl 2 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 CH 2 Cl 2 was added. After 20 min, the mixture was filtered through silica gel, washing with
CH
2 C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1 H NMR and MS [(M H) 417] confirm the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 368 Step 6 I /Bu Oz S -Bu OMe
F
C
25
H
33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide (110.6g/265.5mmol) and CH 2 C12 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K 2
CO
3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgS04), filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1 H NMR confirmed the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 369 Step 7 0 O
S
Bu Bu
F
SOH
OMe
C
2 5
H
3 3 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35g/208.1mmol) was added via addition funnel. After lh, aq/ HC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgS0 4 filtered, and concentrated in vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60g/ combined yield: H NMR confirmed the desired product.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 370 Step 8 0 o
S
Bu Bu Me,N
OH
OMe
C
2 7
H
3 9 0 4 NS fw=473.67 A Fisher porter bottle was fitted with N 2 line and magnetic stirrer. The system was purged with N 2 The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (17.lg/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaC1, dried (MgSO 4 filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1 H NMR confirmed the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 371 Step 9 0
S
Bu Bu Me,N
B
SOH
OH
C
2 6
H
3 7 0 4 NS fw=459.64 A 250-mL, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.62g/14.0mmol) and CHC1 3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2
CO
3 (100 mL).
After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaC1, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1 H NMR confirmed the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTI/US97/04076 372 Step ovo Bu Bu
(H
3 C),N Bu
OH
N
In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 mmol,4.12g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/l% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec and HI NMR) SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 373 Step 11
S
Bu Bu
(H
3
C)
2 N Bu
OH
N
The product from step 10 0.57gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mis of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9 H NMR).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 374 Example 1401 Step 1
OH
OMe
F
C
14
H
13 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N 2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3 -methoxybenzyl.chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining- reflux.
After 15 h. refluxing, the mixture was cooled to room temperature and poured into H 2 0 (2.5 After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min.
The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All aqueous KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried over MgSO 4 filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT[S9/04076 375 (449.0g/39% yield), 120-130 C/50mtorrHg. 1H NMR and MS H) 233] confirmed desired structure.
Step 2
S
/CH3 0
N-CH
3 OMe
F
C
17
H
18 N0 2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl) -phenol (455.5g/1.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H 2 0 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H 2 0 and saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1 H NMR and MS 320] confirm desired structure.
SulB-siTfU SHEET (RULE 26) WO 97/33882 PCT/US97/04076 376 Step 3
SH
OMe
F
C
14
H
13 0FS fw=248.32 A 12-liter, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h.
Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with H 2 0.
The aqueous extracts were combined, acidified with conc.
HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1H NMR confirmed desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 377 Step 4
OH
S Bu Bu OMe
F
C
25
H
35 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and conc. H 2 S0 4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO 4 filtered, and concentrated in vacuo to give an amber oil (143.94g/85% yield). 1 H NMR and MS H) 419] confirm the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 378 Step 0 Bu S ]Bu OMe
F
C
2 5
H
3 3 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, and mechanical stirrer. The system was purged with N 2 The corresponding alcohol (143.94 g/343.8 mmol) and CH 2 C1 2 (1.0 L) were added and cooled to 0 C.
Pyridinium chlorochromate (140.53g/651.6mmol) was added.
After 6 CH 2 C12 was added. After 20 min, the mixture was filtered through silica gel, washing with CH 2 Cl 2 The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield) 1H NMR and MS H) 417] confirm the desired structure.
Step 6 O0 Bu OMe
F
C
2 5
H
3 3 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 379
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide (110.6g/265.5mmol) and CH 2 C12 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K 2
CO
3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1 H NMR confirmed the desired structure.
Step 7 0
S
OMe Bu
C
25
H
33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35g/208.1mmol) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 380 extracted three times with ethyl ether, dried (MgSO 4 filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor-was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60g, combined yield: 1 H NMR confirmed the desired product.
Step 8 Me 2
N
OMe
C
2 7
H
3 9 0 4 NS fw=473.67 A Fisher porter bottle was fitted with N 2 line and magnetic stirrer. The system was purged with N 2 The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (17.lg/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaCl, dried over MgS0 4 filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1H NMR confirmed the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 381 Step 9 0
S
Bu Bu MeN
OH
OH
C
2 6
H
3 7 0 4 NS fw=459.64 A 250-mL, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.62g/14.0mmol) and CHC1 3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2
CO
3 (100 mL).
After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaC1, dried over MgS04, filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1 H NMR confirmed the desired structure.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 382 Step O O
S
Bu B u
(H
3 C)2N Bu S
OH
N
In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of IN KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom-flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above.
Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/l% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec and HI NMR) SUBSTITUTE SIEET (RULE 26) WO 97/33882 PCT/US97/04076 383 Step 11
S
Bu
(H
3 C),N Bu S 'OH
N
The product from step 10 (0.57gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mis of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9, 'H NMR) BIOLOGICAL ASSAYS The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.
In Vitro Assay of compounds that inhibit IBAT-mediated uptake of r"C1-Taurocholate (TC) in H14 Cells Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 384 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.
On the day of assay, the cell monolayer is gently washed once with 100 p1 assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose 0.2% fatty acid free bovine serum albumin- (FAF)BSA). To each well 50 p1 of a two-fold concentrate of test compound in assay buffer is added along with 50 gl of 6 pM ["C]-taurocholate in assay buffer (final concentration of 3 pM ["C]-taurocholate). The cell culture plates are incubated 2 hours at 37' C prior to gently washing each well twice with 100 l1 40 C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 pl 4° C PBS without (FAF)BSA. To each 200 il of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 385 In Vitro Assay of compounds that inhibit uptake of -Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
In Vivo Assay of compounds that inhibit Rat Ileal uptake of ["CC-Taurocholate into Bile (See"Metabolism of 3a,7p-dihydroxy-7a-methyl-50cholanoic acid and 3a,70-dihydroxy-7a-methyl-5(-cholanoic acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum) 20 ml of warm Dulbecco's phosphate buffered saline, pH (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample 4 C]-taurocholate 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure.
After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30. ml syringe), and then the loop is washed out for 21 min with warm PBS at SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTUS97/04076 386 0.25 ml/min. A second perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.
Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform:methanol After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. et al. (1974) Clin. Chem. 470.
Measurement of Hepatic HMG CoA-Reductase Activity (HMG
COA)
Hepatic microsomes were prepared by homogenizing liver samples in a phosphateisucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 370 C in the presence of "C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HC1 followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting.
(Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 387 Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL LDL) Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol C11, Catalog No. 276- 64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.
Measurement of Hepatic Cholesterol 7-a-Hydroxylase Activity (7a-OHase) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-a-hydroxylase activity by incubating for minutes at 370 C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. et al. (1994) J. Clin. Invest. 93, 2084).
Measurement of Fecal Bile Acid Concentration (FBA) Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram was weighed out and extracted into an organic solvent SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 388 (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3ahydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, et al. (1981) Clin. Chem. 27, 1352).
['H1taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et al.
(Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 pl instead of 100 Il.
Briefly, at room temperature a 190 pl solution containing 2uM 3 H]-taurocholate(0.75 pCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 pl of brush border membrane vesicles (60-120 pg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of ml of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 pm pore) and an additional 5 ml wash with stop buffer.
Acyl-CoA;cholesterol AcyI Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 pM Oleoyl-CoA (0.05 pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 BSA and SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 389 200 pg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 370 C and was terminated by the addition of 8.0 ml of chloroform/ methanol To the extraction was added 125 pg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing.
The chloroform phase was taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.
Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows: SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 390 TABLE COMPOUND IC50 In vitro of Control uM* Inhibition Inhibition Transport of TC in of TC of Alanine Rat Ileum 0.1mm Uptake Uptake 100 uN 100 uM Benzothiaze 2 0 45.4 +-0.7 pine-- 12 3 0 4a 3 34 40 0 72.9± 5.4 0.5 mm 4b 9 18 6 14b 18 14a 13 13 23 60 1 19a 0 19b 8a 41 Mixture of 69 Ba and 8b Mixture of 6 9a. and 9b SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 391 6b 9a 5 0% 25 11M 53-7 +-3.9 Mixture of 13 6a and Mixture of 0.8 14% 6d and 10a PM 21a 37 21~c 52 21b 6c 2 58.5 68.8 at 0.4 InN 6d 0.6 77.7 16.1 mM 30.2 0.15 inN 17 7 50 49.3 7 77.6 62.4 0.2 inN 15 68.6 0.1 4% 10 gM 26.0 +-3.3 26 2 31% 25 87.9 pAM 27 5 7% 2 0 pN 28 8 31% 29 88 @5O0PM4 SUBSTITUTE SHEET (RULE 26) WO 97133882 WO 9733882PCTIUS97/04076 392 96 31 41 @50 IM 37 3 5 JIM 38 0.3 11% 5jim 20.6 1-5.7 49 @50 pM 41 2 0% 20 pM 42 43 1.5 16% 48 2 22% 49 0.15 21% 200 21.2 +-2.7 -57 51 58 20 @50 pM 59 9 59 61 30 175 62 63 9 0 @6 M 64 100 @6 pM *In vitro Taurocholate Cell Uptake Unless otherwise noted =Comparative Example is Example No. 1 in WO 93/16055 SUBSTITU TE SHEET (RULE 26) WO 97/33882 WO 9733882PCT1US97/04076 393 TABLE 6 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H114 Ileal (BBMV) (l iver) intestine cells) Loop IC (50) EC (5 0) IC (50) IC(50) IC COMP. 1 Jim 74 11M 3 p14 20 gM 2 0 IM
EXAMPLE
6d 0.6 p14 3 1 p.M 1.5 pm 25 pM 20 pM 38 0.3 RM 12 pW 2 pM 15 PMy N.D.
49 0.1 PM 12 pxM N.D. 6 piM N.D.
0.1pJim 2 0Wg 0. 8 pM 81M 8p1M Comparative Example is Example No. 1 in WO 93/16055 SUBSTMlJTE SHEET (RULE 26) WO 97/33882 WO 9733882PCTIUS97/04076 394 TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS PARAMETER CONTROL 4% CHOLES- 10.2% TYRAMINE J CPD. NO. WEIGHT (mean SEM, *p<0.05, A-student's t, B- Dunnett' s) day 1 117 114(6) 117(5) day 14 127(3) 127(3) 132(4) LIVER WEIGHT 5.4(0.3) 4.9(0.4) 5.8(0.2) SER.CHOL(rng%) 143(7) 119(4)*A,B 126(2)*A,B HDL-CHOL(mg%) 89(4) 76(3)*A,B 76(1)*AIB VLDL LDL 54(7) 42(3)*A 50(3) TGI(mg%) 203(32) 190(15) 175(11) HEPATIC CHOL(mg/g) 2.5(0.3) i.9(0.1)*A,B 1. 9(0. 1) B HMGCCOA (pm/ing/min.) 15.8(7.6) 448.8(21.6)* 312.9 (37.
A,BB
7a-OHase (pin/mg/miri.) 235.3(25.1 24 HR. FECAL Wt )357.2(28.3)* 291.0(6.0)*A FBA (mM/24H/lQ0g) 2.3(0.1) A, B 2.4(0.04) 6.2(0.8) 2.7 11.9(0.5)*A,B 12. 3 5) *A,
B
SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT[US97/04076 395 TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL PARAMETER CONTROL 20 MPL/DAY CPD. NO. WEIGHT (mean SEM, *p<Q*Q5, A-Student's t, B- Dunnett's) day 1 307 307 (3) day 8 330 310 (4)*A,B LIVER WEIGHT 15.5 14.6 (0.4) SER.CHOL(mg%) 85 84 HEPATIC CHOL(mg/g) 21 (0.03) 2.0 (0.03) HMG COA pm/mg/min 75.1 318.0 (40.7)*A,B 7a-Oflase (pi/mg/min) 281.9 (13.9) 535.2 (35.7)*A,B 24 HR. FECAL WT 5.8 5.7 (0.4) FBA (mM/24H/lO0g) 17.9 L 39.1 Additional taurocholate uptake tests were conducted in the following compounds listed in Table 9.
SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCT/US97/04076 396 Table 9 Biological Data for Some Compounds of the Present Invention Compound Human TC Alanine Uptake Number ICOPercent 1050 inhibition 101 0 1020.8 103 13 0.25___ 104 0.0056____ 105 106 107 14.0 0.063 108 0.3 109 2.0 0.063 110 0.09 ill 112 113 0.1 114 0.19 115 116 0.3 117 12.0 0.625 118 0.4 119 1.3 120 34.0 121 0.068 122 1.07 123 1.67 124 14.0 6.25 125 18.0 126 18 1.25 127 0.55 128 0.7 129 0.035 131 1.28 132 5.4 0.063 133 16.0 134 0. 3 135 22.0 136 0.09 137 2.4 138 139 >25.0 140 141 SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT1US97/04076 397 142 143 0.03 144 0.053 262 0.07 263 0.7 264 0.2 265 2.0 266 267 0.073 268 0.029 269 0.08__ 270 0.12 271 0.07__ 272 0.7 273 274 0.18 275 5.0 @1 0.25 276 0.23 277 0.04 278 3. 279 0.4 280 0.18 281 0.019 282 0.021 283 0.35 284 0.08 285 286 19.0 287 288 10.0 6.25 289 0.23 290 0.054 291 0.6 292 0.046 293 1.9 294 0.013 295 1.3 296 1000 1001 1002 1003 1005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 SUBSTIFhTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 398 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 -0.002 1024 0.002 1025 0.002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042 0.003 1043 0.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 1049 0.003 1050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 SUBSTITUT E SHEET (RULE 26) WO 97/33882 PCTfUJS97I04076 399 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0.-Oos 1080 0.005 1081 0.005 1082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 0..006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 1105 1106 1107 007 1108 1109 08 1110 111 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 400 1114 1117 0.0 1114 1119 1120 1117 0.01 1122 0.011 1123 0.011 1124 0.011 1121 0.012 1126 0.013 1127 0.013 1128 0.011 1129 0.012 1130 1131 1128 1133 0.028 1134 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 1142 1139 1144 0.023 1145 1146 1147 1148 1149 0.039 1150 1141 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.031 1156 0.039 1157 1158 1159 0.06 1160 0.062 1161 0.063 SUB3STITUTE SHEET (RULE 26) WO 97/33882 PCTIUS97/04076 401 1162 0.063 1163 0.09 1164 0.093 1165 1166 0.11 1167 0.12 1168 0.12_ 1169 0.12_ 1170 1171 1172 ____1f73 11i74 OAS__ 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 1182 1183 0.28 1184 1185 1186 0.3 1187 1188 0.35 1189 1190 0,55 1191 0.65 1192 1193 1194 1.6 1195 1.7 1196 1197 2.2 1198 2.5 1199 1200 6.1 1201 8.3 1202 40.0 1203 0 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209 0 0.063 1210 0.14 1211 SUBSTUTE SHEET (RULE 26) WO097/33882 PCTIUS97/04076 402 1212 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 1220 1221 0.041 1222 0.065 1223 0.28 1224 -0.33 1225 0.12 1226 0-.046 1227 0.25 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1233 0.15 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 1249 10.2 1250 0.013 1251 0.62 1252 29.
1253 0.3 1254 0.85 1255 0.69 1256 0.011 1257 1258 0.12 1259 16.5 1260 0.012 1261 0.019 SUBSTITUTE SHEET (RULE 26) WO 97/33882 PCTfUS97I04076 403 1262 0.03 1263 0.079 1264 1265 0.24 1266 0.2 1267 0.29 1268 0.035 1269 0.026 1270 0.026 1271 0.011 1272 0.047 1273 0.029 1274 0.028 1275 0.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1.281 0.055 1282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 1290 0.017- 1291 0.013 1292 0.025 1293 0.019 1.294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1301 0.15 1302 1.4 1303 1304 0.25 1305 0.25 1306 1307 3.1 1308 0.04 1309 1310 1.16 1311 SUBSTMJE SHEET (RULE 26) WO 97/33882 PCT1US97/04076 404 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1318 1319 11.0 0.25 1320 1321 11.1 1322 0.0063 1323 0.0063 1324 0.0008 1325 0.0063 1326 36.0 0.0008 1327 3.0 0.0063 1328 68.0 0.0063 1329 0.0063 1330 9.0 0.0063 1331 57.0 0.0008 1332 43.0 0.0008 1333 0 0.0063 1334 0.0008 1335 38.0 0.0008 1336 45.0 0.0008 1337 0 0.0063 1338 1.0 0.25 1339 0 0.063 1340 9.0 0.063 1341 1.0 0.063 1342 1.0 0.063 1343 1344 1345 13.0 0.25 134,6__ 1347 0.0036 1349 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.014 1360 0.003 1361 0.004 SUBSTITUTE SHEE. (RULE 26) 405 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014 The examples herein can be repeated with similar :.success by substituting the generically or specifically 5 described reactants and/or operating conditions of this invention for those used in the preceding examples.
Novel compositions of the invention are further illustrated in attached Exhibits A and B.
"The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and eauivalents as would be obvious to one skilled in the art are intended to be included 15 within the scope of the following claims.
With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, we note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that we intend each of those words to be so interpreted in construing the foregoing description Vnd/or the following claims.
WO 97/33882 PCTIUS97/04076 406 Exhibit A Table C2: Alternative Compounds #2 (Families Fl0l-F123) 0 )q F1
OH
Family Cpd R 1
=R
2
R
5 (RR)q F101 Fl102 Fl103 Fl104 Fl105 Fl106 F107 F108 Fl109 F110 F1ll F112 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE I CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 Ph p-F-Phrn-F-Php -CH 3 0-Ph i-CH 3 0-Php- (CH 3 2 N-Phn- (CH 3 )2'N-Ph I, P-(CH 3 3 -N-hCH-
(OCH
2
CH
2 2 -O-Phm- (CU 3 3
-N'-CH
2
CH
2
(OCH
2
CH
2 2 -O-Php- (N,Ndimethylpiperazine)
CH
2
(OCH
2
CH
2 2 -O-Ph- CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 SUG)M fffE (HULF 26) WO 97/33882 PCTIUS97/04076 407 F113 F114 F115 F116 F117 F118 F119 F120 F121 F122 F123 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 m-(N,Ndimethylpiperazine)
CH
2
-(OCH
2
CH
2 2 -O-Phm-F-Php-CH 3 0- 3,4, dioxy-methylene-Phm-F-Php-F-Phm-CH30p-F-Ph- CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 4-pyridine N-methyl-4-pyridinium 3-pyridine N-methyl-3-pyridinium 2-pyridine p-CH 3 02C-Ph- Similar families can be generated where R 1 is not equal to
R
2 such as R 1 Et and R 2 n-Bu, but (Rx)q is chosen from table C1.
SUBSTITUTE SHEET (RULE 26) WO 97/33882
(H
3
C)
2
N
PCT[US97/04076 408 Exhibit B 0, -ss 01 02 s OH
(H
3 C)N 0 1 G 02 No(CHCH)) 0 N() SUBSTITUTE SHEET (RULE 26) WO 97/33882 WO 9733882PCT1US97/04076 409
*N(CH
3 3 (D
I
I G
H
3
CO
SUBSTITUTE SHEET (RULE 26) WO 97/33882 410 02 0, RS3 HIC H 2
N
b H
H
3 CO\No
F
0, 02 S 39S H,N H 3
CO
H
3
C
02 HO 0, R 41
"**OH
I T
O
PCTIIJS97/04076 SUBSTITUTE SHEET (RULE 26)

Claims (20)

1. A compound of formnula [f]n 8~ SR 91 2 R (Rx)q 3(I 6 5 4 R R 3 R 6 R 5 R4 wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more sub stituents selected from the group consisting of OR 9 N1R 9 R 10 N+R 9 RIORwA, SR, S+R 9 R 10 A, P-'RR 1 A, S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR 9 WNR 9 R' 0 A, S, SO, 802, S R9A, P+R 9 R 1 0 KA, or phenylene, wherein R 9 R1 0 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylam-moniumalkyl, and arylalkyl; or R1 and R 2taken together with the carbon to which they are attached form C 3 -CI 0 cycloalkylidene; 411 R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 SR', S0 2 R 9 and SOR 9 wherein R9 and R 10 are as defined above; or Rand R 4 together form =NOR", =NNR R =NR or =CR R, wherein R1 and R 1 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R' 0 SR 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 wherein R 9 and R1 0 are as defined above, provided that both R 3 and RW cannot be OH, NH 2 or SH, or R1 and R 12together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R6 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9, SR9, S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylailcyl, quaternary heterocycle, quatemnary heteroaryl, halogen, oxo, OR'1 3 .9NR1 3 SR' S(O)R' 3 SO 2 R' 3 S0 3 R' 3 NRI 3 OR ,NR1 3 NRI 4 NO 2 C0 2 R' 3 ~CN, OM, SO 2 OM, S0 2 NR' 3 C(O)NR 3 R 1 C(O)OM, COR' 3 P(O)R' 3 R'
010.P+R13 R14 RA-,P(OR1 3 )OR 1 4 S+1 4A-, and N+9R R2 A-, A- is a pharmaceutically acceptable anion and M is a pharmaceutically 0. 25 acceptable cation, .0 0 00.: said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR', SR', S(O)R 7 S0 2 R 7 S0 3 R 7 C0 2 R 7 CN, oxo, CONR', N+R 7 R 8 R 9 N, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)kR'R, P R 7 R N9, an ()(0R 7 )0R 8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, WR, N+R 7 R 8 N S, SO, S02, S+R 7 A, PR 7 P(O)R 7 P+R 7 R 8 A, or phenylene, 412 and R" 3 R" 4 and R" 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl., heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl., heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NP?, N+R 9 R 0 S, SO, SO,, S+R 9 A, PR 9 P+R 9 R OA- P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R' 3 R' 4 ,and R 1 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R' 0 N+R 9 R R"AN, SR 9 S0 2 R9, SO 3 R9, 9 910 16 17 oxo, CO 2 R9, CN, halogen, CONR 9 R' 0 SO 2 OM, S0 2 NRR1', P O(OR )OR P+R 9 R' 0 S+R 9 R' 0 and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or 14 R and R1 5 together with the nitrogen atom to which they are attached, form a cyclic ring; R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR3 NR' 3 SR' 3 S(O)R' 3 S(O) 2 R' 3 S0 3 R' 3 S+R1 R' 4 A, NR' 3 0R 1 4 NRD 3 NR] 4 NO 2 C0 2 R 1 3 CN, OM, SO 2 OM, S0 2 NR 13 R 1 4 25 N'C(O)R' 3 RR, RC(O)R 1 3 C(O)OM, COR' 3 OR' 8 S(O)nNR' 8 NR1 3 R' R 4 N+R 9 R"1R'A, P+RR1R'A, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalicyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR, NR 9 R1 0 N+R 9 R"R'1 2 NA, SR 9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO 2 OM, 9 10 1 6 R 7 PRR 1' 2 A~ 9 n SO 2 NRR', PO(OR )ORPRR1 ,SRROo n wherein R' 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, 413 wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR, NRR', N+R 9 R"R 2 SR 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 3 R 9 S0 2 0M, SO 2 NIR 9 R' 0 P O(OR' 6 )OR' 7 and C(O)OM, wherein in RW, one or more carbons are optionally replaced by 0, NR' 3 +R' 3 R 4 S, SO, SO 2 S+R' 3 N, PR' 3 P(O)R' 3 P+R' 3 R'A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N+-R 9 R' 0 S, SO, S02, S+R 9 PR 9 P+R 9 R' 0 K, or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR NR1 3 SR' 3 S(O)R' 3 S0 2 R' 3 S0 3 R 13 OR 3 R' 4 NR NO 2 C0 2 R' 3 CN, OM, S0 2 0M, S0 2 NR 1 R, C(O)NR 3 R 1 4 C(O)OM, COR' 3 P(O)R 13R. 4 P+R 1 3 R 4 R 5 P(OR1 3 )OR 1 4 *S+R1 3 R 14 K, and N+R 9 R1 R 12A, :provided that R 5and R 6cannot be OH, and both R 5 and R6 cannot be SH; provided that when R 5 or R 6 is phenyl, only one of R 1 or R 2 is H; and provided that when q I and R' is styryl, anilido, or anilinocarbonyl, only one of R 5 or R 6 is alkyl. 2. A compound of claim 1, wherein R 5 and R 6 are independently selected 25 from the group consisting of aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl., pqlyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl., halogen, oxo, OR 1 3 NR 13 R 1 4 SR', S(O)R 1 3 S0 2 R' 3 S0 3 R' 3 NR1 3 OR 14 INR 13 NI 4 R' 5 NO 2 C0 2 R 13 CN, OM, S0 2 0M, SO 2 NR' 3 R 4 C(O)NR 3 R 1 4 C(O)OM, COR 1 3 P(O)R 3 R' 4 P RR K' 5 P(OR' 3 )OR' 4 S+R' 3 R. 4 and N+R 9 R' 1 R' 2 A, 414 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 N 4 R 7 R 8 A, S, SO, SO,, S+R 7 K, PR 7 P(O)R 7 P+R 7 R 8 A, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be fuirther substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 SR 7 S(O)R 7 S0 2 R 7 S0 3 R 7 C0 2 R 7 CN, oxo, CONR 7 N+R 7 R 8 R 9 K, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 P+R 7 R 8 and P(O)(0R 7 )0R'. 3. A compound of claim 2, wherein R5 or R6 has the formula -Ar-(R~ wherein: :t is aninteger from 0to Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more Ryare independently selected from the group consisting of H, 9 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR, SR S(U)K S02R, and S03R, :25 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 NR 1 3 R 1 SR 13 S(O)R 1 3 S02R 1 3 S03R 1 3 NR 1 3 OR 1 NR 1 3 NR 1 4 R 1 N02, C02R 1 3 CN, OM, S020M, S02Nk 1 R R, C(O)N1R 1 3 R 1 C(O)OM, C0R 1 3 P(O)R 1 R 1 4 P R 1 R15A-, P(0R 13 )OR 1 R and N+R 9 R 1 R 2 415 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 R 8 SR 7 S(O)R 7 S02R 7 S03R 7 C02R 7 CN, oxo, CONR 7 R 8 N+R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quatemary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 pR 7 R8A and P(O)(OR 7 )OR 8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 N R 7 R 8 S, SO, SO2, S+R 7 PR 7 P(0)R 7 P R 7 R 8 or phenylene. 4. A compound of claim 3, wherein R 5 or R 6 has the formula (II) ::7 (II) (R )t 5. A compound of claim 4, wherein n is 1 or 2. 6. A compound of claim 5, wherein one of R 7 or R 8 is H and the other of R 7 or R 8 is alkyl. 7. A compound of claim 5, wherein both R 7 and R 8 are H. 8. A compound of claim 7, wherein R 1 and R 2 are independently selected from the group consisting of H and alkyl. xS=T 9. A compound of claim 8, wherein said alkyl is a 416 l lp L U V a aa 9 95 *9 C1-Co1 alkyl. A compound of claim 8, wherein R' and R 2 are both alkyl.
11. A compound of claim 10, wherein said alkyl is a C1-C10 alkyl.
12. A compound of claim 11, wherein said alkyl is a C 2 -C 7 alkyl.
13. A compound of claim 12, wherein said alkyl is a C 2 -C 4 alkyl.
14. A compound of claim 13, wherein said alkyl is independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. A compound of claim 8, wherein R 1 and R 2 are each n-butyl.
16. A compound of claim 8, wherein one of R1 and R2 is ethyl and the other ofR 1 and R 2 is n-butyl.
17. A compound of claim 15, wherein q is 1, 2, or 3.
18. A compound of claim 16, wherein q is 1, 2, or 3.
19. A compound of claim 17, wherein q is 1 or 2. A compound of claim 19, wherein q is 1.
21. A compound of claim 18, wherein q is 1 or 2.
22. A compound of claim 21, wherein q is 1.
23. A compound of claim 19, wherein R 3 and R 4 are independently selected from the group consisting of H and OR 9 417
24. A compound of claim 21, wherein R 3 and R 4 are independently selected from the group consisting of H and OR 9 A compound of claim 23, wherein R 9 is H.
26. A compound of claim 24, wherein R 9 is H.
27. A compound of claim 25, wherein one or more R x are in the 8-, or 9-position of the benzo ring of formula
28. A compound of claim 26, wherein said Rx is in the or 9- position of the benzo ring of formula
29. A compound of claim 27, wherein said Rx are in the 7- and 9- 15 positions of the benzo ring of formula
30. A compound of claim 28, wherein said R x is in the 7-position of the benzo ring of formula 20 31. A compound of claim 29, wherein said one or more R x are independently selected from the group consisting of alkyl, aryl, cycloalkyl, 13 13 14 heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 13 NR 13 R 1 4 SNR 13 NR 1 4 R 1 5 N+R 9 R 1 1 R 12 A SR 13 S+R 1 3 R 14 CO2R 13 NR 4 C(O)R 3 and NRI4C(O)R 3 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NR 9 R 10 N+R 9 R 1 1 R 12 A SR 9 S(O)R 9 S02R 9 S03R 9 oxo, C02R 9 CN, halogen, CONR 9 R 10 SO 2 OM, SO 2 NR 9 R 1 0 PO(OR 6 )OR 7 p+R 9 R 1 1 R 12 A S+R 9 R'OA-, or C(O)OM, and wherein in Rx, one or more carbons are optionally replaced by O, NR 13 NR1 3R14A-, S, SO, S02, S R13A-, PR13, P(O)R13, R13R14 phenylene, 'amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and
418- wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR, N+ S, SO, S02, S R PR, P R R 1 0 A, or P(O)R 9 32. A compound of claim 30, wherein said Rx is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 13 NR 3 R 1 NR~ 3 NR 14 R 5 'NR R 1 1 R 1 A, SR 1 3 S R1 3 R 14 13R13 S R C2, NR1 4 C(O)R' 3 and NR' 4 C(O)R 3 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NRR N+R 9 R 1 lR 1 2 A, SR 9 S(0)R 9 S02R S03R 9 oxo, C02R 9 CN, halogen, CONR 9 R 1 0 S0 2 0M, SO 2 NR 9 R' 0 PO(OR' 6 )OR' 7 P +R 9 R1 1 R 1 2 A, S+R 9 R 10 N, or C(O)OM, and wherein in RX, one or more carbons are optionally replaced by 0,NR1 N'R 1 3 R 1 5 S0, S02, S R PR 1 3 P(O)R' 3 p+ R 1 R 4 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR, N R R 1 0 5, SO, S02, S R PR 9 P R R 0 or P(0)R 9 33. A compound of claim 3 1, wherein said one or more Rx are independently selected from the group consisting of polyether, OR'1 3 NRR 1R 4 and N +R 9 R 1 1 R 12 A-. 34. A compound of the claim 32, wherein said Rx is selected from the group consisting of polyether, OR NR' 3 R'5 and N+R R 1 R 1 2 A. A compound of claim 33, wherein said one or more Rx are independently selected from the group consisting of OR 3 and N4R'R 14 got* 09-0 .000 0..9 419 36. A compound of claim 34, wherein said Rx is independently selected from the group consisting of OR 13 and NR 3 R14. 37. A compound of claim 35, wherein R 13 and R 1 4 each methyl. 38. A compound of the claim 36, wherein R 13 and R 14 each methyl. 39. A compound of claim 31, wherein one or more R Y are independently in the 3- or the 4-position of the phenyl ring of formula (II). A compound of claim 32, wherein one or more Ry are independently in the 3- or the 4- position of the phenyl ring of formula (II). 41. A compound of claim 39, wherein t is 1 or 2. 42. A compound of claim 40, wherein t is 1 or 2. 0y 43. A compound of claim 41, wherein said one or more R y are 9 independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR 13 R 14 NR1 4 C(O)R' 3 and OR 13 9 wherein alkyl and polyether can be further substituted with SO3R, N R 9 R 1 1 R 12 A and quaternary heteroaryl. 44. A compound of claim 42, wherein said R Y is independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR 13 R 14 NR14C(O)R3, and OR 13 9 wherein alkyl and polyether can be further substituted with SO3R N+R 9 R 1 1 R 12A and quaternary heteroaryl. 420 A compound of claim 43, wherein said one or more R y are independently selected from the group consisting of alkyl, polyether, fluoride, NR 1 3 R 14 NR' 4 C(O)R' 3 and OR 13 wherein alkyl and polyether can be further substituted with SO3R 9 N R 9 R 1 1 R 12 A and quaternary heteroaryl. 46. A compound of claim 44 wherein said R Y is independently selected from the group consisting of alkyl, polyether, fluoride, NR 13 R 14 NR14C(O)R 3 and OR 1 3 wherein alkyl and polyether can be further substituted with SO3R N R 9 R 1 1 R 12 A and quaternary heteroaryl. 47. A compound of claim 45, wherein said R 1 3 and R 14 are alkyl, wherein alkyl can be further substituted with SOR9, NR9R1R1 2 A, and 15 quaternary heteroaryl. 48. A compound of claim 46, wherein said R 9 and R 10 are alkyl, wherein alkyl can be further substituted with SO 3 R 9 NR 9 R 1 R 12 A, and quaternary heteroaryl. 49. A compound of claim 47, wherein n is 2. 50. A compound of claim 48, wherein n is 2. 51. A compound of claim 49, wherein said OH group is in a syn relationship to said structure of formula (II). 52. A compound of claim 50, wherein said OH group is in a syn relationship to said structure of formula (II). 421 53. A compound having the formula: 0 N(CH 2 CH 3 3 54. A compound having the formula: 0 *0:00 00 V, 0: 060 000* 6* 0 00 O0 09 0 S 6:00 0:0 N S0 3 H H A compound having the formula: 422 OH N 56. A compound having the formula: [A] to of.:* [A1 57. A compound having the formula: 423 S0 3 H 58. A compound having the formula: 0 .9 *0 9 0 0 no. 0 0 0 0I a 9 0 0*0 0 0*0 00 0 00 [A] A compound of claim 3 1, wherein n is 1. A compound of claim 59, wherein.Ry is H. A compound of claim 60, having the formula 424 OH i S SS t 62. A compound of claim 4, wherein R' and R 2 are independently selected from the group consisting of H and alkyl. 63. A compound of claim 62, wherein said alkyl is Ci-Clo alkyl. 64. A compound of claim 63, wherein said alkyl is C 2 -C 7 alkyl. A compound of claim 64, wherein said alkyl is C 2 -C 4 alkyl. 66. A compound of claim 65, wherein R' and R 2 are independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. 67. A compound of claim 4, wherein R 3 and R 4 are independently selected from the group consisting of H and OR 9 68. A compound of claim 67, wherein R 9 is H. 69. A compound of claim 4, wherein n is 2. A compound of claim 3, wherein R 3 and R 4 are independently selected from the group consisting of H and OR 9 ST1 71. A compound of claim 70, wherein R is H. 425 72. A compound of claim 3, wherein one of R 7 or R 8 isH. 73. A compound of claim 72, wherein both R 7 and R 8 are H. 74. A compound of claim 3, wherein said one or more Rx are independently selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 1 3 NR 1 3 R 1 NR 13 NR 1 4 R 1 5 ,N+R 9 R 1 1 R 12 KS 1 3 1 3 R 1 4 ,C2 1 3 13~() and NR1 4 C(O)R' 3 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NR R 10 NR 9 R 1 R 1 K,SR, S(O)R. S02R S03R oxo, C02R CN, halogen, CONIR R 1 S0 2 0M, S0 2 NR'R1 0 PO(0R 16 )0R 17 p+ R 9 R1 1 R 1 2 A, S+R 9 R' 0 or C(O)OM, and wherein in RX, one or more carbons are optionally replaced by 0, NR 1 +R3R1A-SSS2 +R 13A, PR 13, P(O)R 1 3 p+R1 3 R1 4 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and .~wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, 999 9. and carbohydrate, one or more carbons are optionally replaced by 0, NR NR9R1 K S, SO, S02, S+9- R, P+ or P(O)R 9 A compound of claim 74, wherein said one or more R' are independently selected from the group consisting of polyether, OR" 3 NR' 3 R' and N+R 9 R. 11 R 1 2 A-. .76. A compound of claim 75, wherein said one or more R.x are independently selected from the group consisting of OR" 3 and NR 3 R 1 4 77. A compound of claim 76, wherein R 1 3 and R 1 4 are each methyl. !D 426 78. 'A compound of claim 3, wherein one or more Ry are independently in the 3- or the 4-position of the phenyl ring of formula (II). 79. A compound of claim 78, wherein one or more Ry is selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, 9 10 9 NR R, and NC(O)R, wherein alkyl and polyether can be substituted with S03R, N'R 9 R1 1 R 1 2 A, and quaternary heteroaryl. A compound of claim 79, wherein R 9 and R 0are alkyl. 81. A compound of claim 80, wherein one or more Ry is selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR R 0 and NC(O)R. 82. A compound of claim 1, wherein said one or more RX are independently selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 13 NR 1 3 R 1 NR 1 3 NR 1 4 R 1 N~R R 1 R 1 A, SR 13 S R 1 3 R 1 C02R 1 3 RI 4 C(O)R~ 3 and NR1 4 C(O)R 13 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR N1R R 1 N~R R 1 R 1 SR 9 S(O)R S02R S03R oxo, C02R CN, halogen, CONR R 1 SO 2 OM, S0 2 NR 9 R 10 PO(0R 16 )OR 1 7 P+R 9 R 1 'R 12 A, S+R 9 R 1 0 or C(O)OM, and wherein in RX, one or more carbons are optionally replaced by 0, NR 1 N R 1 3 R. S, SO, S02, S R 1 3 PR 3 P(O)R, P+R 1 3 R 4 A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalicyl, and 9. 9 3* 93 a 9 4 *33* 9 9 9 9 3 9 4 ~9 25 427 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 N+R 9 R 10 S, SO, S02, S R 9 PR 9 P+RR 1 0 or P(O)R 9 83. A compound of claim 1, wherein n is 1 or 2. 84. A compound of claim 83, wherein n is 2. A compound of claim 1, wherein R' and R 2 are independently selected from the group consisting of H and alkyl. 86. A compound of claim 85, wherein said alkyl is Ci-Cio alkyl. 87. A compound of claim 86, wherein said alkyl is C 2 -C 7 alkyl. 88. A compound of claim 87, wherein said alkyl is C 2 -C 4 alkyl. 89. A compound of claim 88, wherein R' and R 2 are independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. A compouiid of claim 1, wherein R 3 and R 4 are independently selected from the group consisting ofH and OR 91. A compound of claim 90, wherein R 9 is H. .8 o 7 2 92. A compound of claim 1, wherein one of R or R is H. .93. A compound of claim 92, wherein both R 7 and R 8 are H. t 94. A compound of the formula (III) "~OF 428 O S Oe Od. (R)t (RyA)u (RxA)r (RX)q wherein: q and r are independently integers from 0 to 4; d and e are independently integers from 0 to 2; t and u are independently integers from 0 to 4; R IA, R 2 and R2A are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituent selected from the group consisting of OR 9 NR 9 R 1 0 N4R 9 RIORw A, SR 9 S RA-. P R 9 RIoR"A, S(O)R 9 S02R 9 S03R 9 C02R 9 CN, halogen, oxo, and CONR 9 R 1 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, 9 aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR, N+R 9 R 1 0 S, SO, S02, S R 9 P R 9 R 1 0 or phenylene, wherein R 9 R 10 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or 20 R' and R2 taken together with the carbon to which they are attached form C 3 -C 10 cycloalkylidene, or R1A and R 2 A taken together with the carbon to which they are attached form C 3 -C 10 cycloalkylidene; 429 15 9 9 .9 9. 9. 9 9 9 *9*9 i* 9 9 9**9 *9 *9 R 3 R 3 A, R4, and RA are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR R 1 0 SR, 9 9 0 S(O)R S02R and S03R .,wherein R9 and R1 are as defined above; cfr Rand R4 together form =NOR 1 1, =NNR 1 1 R 1 -NR 9 or =C 1 1 R 12 ,o R 3 A and R 4 A together form =NORI 1 -NNR 1 1 R 1 =NR ,or =CR 1 1 R 1 wherein R 1 and R 1 are independently selected from the group consisting of H, alkyl, alkenyl, alkyriyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, 9 heterocycle, carboxyalkyl, carboalkoxyallcyl, cycloalkyl, cyanoalkyl, OR NR R 1 0 SR 9 S(O)R 9 S02R 9 S03R 9 C02R 9 CN, halogen, oxo, and CON4R 9 R 1 0 wherein R 9 and R 1 0 are as defined above, provided that both R 3 and R4cannot be OH, NH2, and SH, or RiIand R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; wherein A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R 7 RA R8, and R IAare independently selected from the group consisting of hydrogen and alkyl; and one or more RX and RA are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkcyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 NR 1 3 R 1 SR 13 S (O)R 1 3 S(O)2R 1 3 S03R 1 3 S R 1 3 R 1 NR 1 3 OR 4 1NR 1 NR 1 4 R 1 N02, C02R 1 3 CN, OM, SO2OM, SO2NR 1 3 3 R 14 NR 14 C(O)R 1 3, C(O)NIR 1 3 3 R 14 NR14C(0)R1 3, C(O)OM, C0R 1 3 OR 1 8 S(O)nNR 18 NR 1 3 R 1 NR 1 8 OR 1 N R 9 R 1 R 1 A, P +R 9 R 1 1 R 1 2 A, amino acid, peptide, polypeptide, and carbohydrate, 430 wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR NR R 1 0 N+R 9 Rl' AR 1 2 SR 9 S(O)R S02R S03R oxo, C02R CN, halogen, CONR 9 R 10 S020M, S02NR R 1 0 PO(OR 1 6 P RR 1 1 R 1 A, S+R 9 R 1 0 K, or C(O)OM, and wherein RI 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituent selected from the group consisting of OR 9 NR R 1 N'R 9 R 1 1 R 1 SR 9 S(O)R 9 S02R S03R oxo, C02R CN, halogen, CONR R 1 0 S03R S020M, S02NR 9 R 1 0 PO(0R 1 6 )0R 1 and C(O)OM, wherein in Rx and R'A, one or more carbons are optionally replaced by 0, 13 13 14S+R 1 3 A- 13+134 NRl, N R 1 3 R 1 5, SO, SO2, S R P(O)R13, PR R A phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or :polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, 4. and carbohydrate, one or more carbons are optionally replaced by 0, NR, R N RR 1 S, SO, S02, S R PR, P R 9 R. 1 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally .4....substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alcynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, *4.4.arylalkyl., halogen, oxo, OR 1 3 NR 1 3 R 1 SR 1 3 5 S(O)R 1 3 S02R 1 3 S03R 1 3 NR 1 3 0R 1 NR NR 4 R 1 5 N02, C02R 1 3 CN, GM, S020M, S02NR 1 3 R' C(O)NR 1 3 R 1 C(O)OM, C0R 1 3 P(O)R 1 3 R 1 P R 1 3 R 1 P(0R 13 )OR 1 4 S+R1 3 R' 14&, and NR 9 R 1 1 Rl 2 A, R1 9 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne 431 diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by 0, Nk7, N+R7R8, S, SO, S02, S+R7R8, PR7, P±R7RS, phenylene, heterocycle, quatamary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy-diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 NR 1 3 R 1 SR 1 3 S(O)R 1 3 S02R 1 3 S03R 1 3 N1R 1 3 OR 1 NR 1 NR 1 4 R 1 N02, C02R 1 3 CN, OM, S020M, S02N~R 13 R 1 C(O)NR 1 3 R 1 C(O)OM, C0R 1 3 P(O)R 1 3 3 R 1 4, P +R 1 3 R 1 4 4 RI 5A-, P(0R 1 3 )OR 1 4 S+R 1 3 R14A, and N+R 9 R I R 1 2 A-; wherein one or more Ry and R YA are independently selected from from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, 9 9 9 99 quaternary heterocycle, OR 9 SR S(O)R S02R and S03R wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 3, N1R 13 R 14 SR 13 :20 S(O)R 13 S02R 1 3 S03R 1 3 NR 1 3 0R 1 NR 1 3 NR 1 4 R 1 N02, C02R 1 3 CN, OM, SO2OM, SO2NIR'R 1 4 C(O)NR 1 3 R 1 C(O)OM, C0R 1 3 P(O)R 1 3 R 1 4 3 413) 14 13 14 1 1 P R) I5- (ROR ,SR R A-,and NRRRA- wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloatkyl, and heterocycle can be further substituted with one or more substituent 7 7 00*25 groups selected from the group consisting of OR' NIR R SR S(O)R S02R, 0SS03R C02R CN, oxo, CONR R N+R R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quatemary heterocycle, quaternary heteroaryl, P(O)R R P R R and P(0)(0R 7 and ~ST~ wherein said alkyl, alkenyl, alkcynyl, polyallcyl, polyether, aryl, haloalkyl, y cycloalkyl, and heterocycle *can optionally have one or more carbons replaced by 432 0, NR 7 N+R7R8A-, S, SO, S2, SR 7 PR 7 P(O)R 7 p+R 7 R 8 or phenylene. A compound of claim 94, wherein R 1A R 2 and R 2 A are independently selected from the group consisting of H and alkyl. 96. A compound of claim 95, wherein RIA, R 2 and R 2 A are independently selected from the group consisting of H and Ci-Clo alkyl. 97. A compound of claim 96, wherein said alkyl is a C 2 -C7 alkyl. 98. A compound of claim 97, wherein R 1A R 2 and R 2 A are independently C 2 -C 4 alkyl. 99. A compound of claim 98, wherein R 1 R A, R 2 and R 2 A are independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. 9 100. A compound of claim 94, wherein R 3 R 3 A, R 4 and R 4 A are 20 independently selected from the group consisting of H and OR 9 *9 *t 101. A compound of claim 100, wherein R 9 is H. 102. A compound of claim 94, wherein R 7 R 7 A, R 8 and RSA are H. *I 103. A compound of claim 94, wherein d and e are independently 1 or 2. 104. A compound of claim 103, wherein d and e are both 2. 9 o 105. A compound of claim 94, wherein one or more R x and one or more R are independently selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 1 3 N 3 R 1 4 433 N7 R 1 NR 14 R 1 5 N+R 9 R 1 1 R 1 2 A, SR 1 3 S +R 13 R 1 4 C02R 1 3 NR1 4 C(O)R'1 3 and NR 14 C(O)R 13 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with, OR NR R 10 N+R 9 R 1 1 R 1 A, SR, S(O)R 9 S02R S03R oxo, C02R 9 CN, halogen, CONRR 1 S0 2 0M, SO 2 NR 9 R' 0 PO(OR' 6 )OR' 7 P+R 9 R 1 R 1 2 K, S+R 9 R 10 K, or C(O)OM, and wherein in Rx, one or more carbons are optionally replaced by 0,NR1 N+R 1 3 R 1 S, SO, S02, S R 1 3 PR 1 3 P(O)R' 3 P+R 13 R 4 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, N7R 9 N+R 9 R 1 0 S, SO, S02, S+R 9 PR 9 P+R 9 Rl OA-, or P(O)R 9 106. A compound of claim 94, wherein one or more Ry and one or more R YA are independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR 1 3 R 1 NR 14 C(O)R and OR 13 9 wherein alkyl and polyether can be fuarther substituted with S03R N R 9 R1 1 R 12 and quaternary heteroaryl. 107. A compound of claim 94, wherein R1 9 is selected from the group consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and polyalkoxy .diyl, wherein alkane diyl and polyalkane diyl can optionally have one or more carbon replaced by 0, NR7, N+R7R8, S, SO, S02, S±R7RS, PR7, P+R7R8, or -phenylene. 9.25 108. A compound of claim 107, wherein R1 9 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by 0, NR 9 N +R 9 R 1 0 S, SO, S02, S+R 9 R 1 0 PR 9 434 P +R 9 R 1 0 phenylene, amino acid, peptide, polypeptide, carbohydrate, or polyalkyl. 109. A compound of claim 108, wherein R 1 RIA, R 2 and R 2 A are inde pendently selected from the group consisting of H and alkyl. 110. A compound of claim 109, wherein R IA, R 4 and W 4 A are independently selected from the group consisting of H and OR 9 111. A compound of claim 110, wherein R 9 is H. 112. A compound of claim 111, wherein R7, R 7 A R 8 and R 8A are each H. 113. A-compound of claim. 112, wherein d and e are independently 1 or 2. 114. A compound of claim 113, wherein one or more R and one or more RA~ are independently selected from the group consisting of alkyl, aryl, so 20 cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 1 3 NR 1 3 R 1 4 *NR 1 3 NR 1 4 R 1 N R R 1 1 R 1 K,SR 13 'S R 1 R 1 C02R 1 3 NR1 4 C(O)R 3 and NR1 4 C(O)R 13 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NR R 1 0 NR 9 R 1 R 1 K,SR, Ge025 S(O)R S02R S03R oxo, C02R CN, halogen, CONR R 1 S0 2 0M, SO 2 RR 9 R' 0 PO(OR 6 )0R 17 P+R 9 R 1 1 R 1 2 A, S+R 9 R 10 or C(O)OM, and 00 0 towherein in Rx, one or more carbons are optionally replaced by 0, NR 1 N+R 13 R 1 4 S, SO, S02, S R 13 PR 1 3 P(O)R' 3 P+R 13 R 1 4 A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and 435 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 N+R 9 R 10 S, SO, S02, SR 9 PR 9 P R 9 R 1 0 or P(O)R 9 115. A compound of claim 114, wherein one or more R Y and one or more RyA are independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR 13 R 14 NR 4 C(O)R 3 and OR 13 wherein alkyl and polyether can be further substituted with SO3R 9 N R 9 R 1 1 R 12 and quaternary heteroaryl. 116. A compound of claim 115, having the formula: PEG H H o 117. A compound of the formula (V) 117. A compound of the formula (IV) 436 Ri 4)r R 3id3 R JR2A2M R1,AadRaeideednl eetdfomtegopcnitn of HakR leyaknl aolyaklrl rllyakxakxakl diryaio alytho (plaky rl$adcclakl R R 0 a d le whei alkyl, alkenyl, alkyn olyl, alkylaryl, aalky, alkoxyalk olyalkyl, aloylydaklmnaklho plaklaryl, and cycloalkyl optionally haeoeoamrrabnsrpaeeb ,N 9 99 NOR NR 1 0 RSORv, SR 9 P+RRA-, or9RR phenylene,2 6066 wherein RalkRl, and R arenl lklrl indpenenty elected from the group a *9 0 consistingdofyH, lkyl, otaly havekynl coakylcaryon, race heeoyc,N aRnmoiAl-lS,aSOkySammoSiumalk, an aiyla10 yl- or eyee R1 and R 2 taken together with the carbon to which they are attached form C 3 -CIO cycloallcylidene, or 437 6e.e 9. 9. 6 6 9* 9 *9 9. 9 S9 0S 9 9 0 9.99 99 9 9 9 6 *9*9 S 99 9 Se 25 RIAand R 2 A taken together with the carbon to which they are attached form C 3 -CIO cycloalkylidene; 3 3A4 R ,R AWR,and RA are independently selected from the group consisting* of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR R 1 0 SR, 9 9 9 9 1 S(O)R S02R and S03R wherein R and R1 are asdefined above; or Rand R 4 together form =NOR 1 -NNR 1 1 R -NR 9 or =CR 1 1 R 1 or* R 3 A and R Atogether form =N0R 1 1 4NNR 1 1 R 2 NR 9 ,o =CR 1 R 12 wherein R 1 1 I and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, 9 heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, -cyanoalkyl, OR NR 9 R 1 0 SR 9 S(O)R 9 S02R 9 S03R 9 C02R 9 CN, halogen, oxo, and CONR 9 R 1 0 wherein R 9 and Rare as defined above, provided that both R 3 and R4cannot be OH, NH2, and SH, or Rl1and RI2together with the nitrogen or carbon atom to which they are attached form a cyclic ring; wherein A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R ,RkA ,R 8 ,andR"A are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl, OR 1 3 N1R 13 R 1 SR 1 S (O)R 1 3 S(O)2R 1 3 S03R 1 3 SIR 13 R 1 4 NR 1 3 0R 1 4 N R 1 3 NR 1 4 R 1 5 N02, C02RI 3 CN, OM, SO2OM, S02NR 1 3 R 1 4, NR' 4 C(0)R 1 3, C(0)KR 1 3 R 1 4 NR14C(O)Rl 3, 438 C(O)OM, C0R 1 3 OR 18 S(O)nNR 18 NR 1 3 R is, NR 1 8 OR 1 4 N +R 9 R 1 1 R 1 2 KA, P +R 9 R 1 I R 1 2 amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR NR R NRR 1 1 R 1 K,SR 9 S(O)R S02R S03R oxo, C02R, CN, halogen, CONR R 1 0 S020M, S02NRR, PO(OR' 6 )OR P +R9R.1 R 1 2 A, S R N"A, or ()Man w .herein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituent selected from the group consisting of OR, 'NR R 1 0 N+R 9 R 1 'R 1 2 SR 9 S(O)R 9 S02R 9 S03R 9 oxo, C02R 9 CN, halogen, CONR R 1 0 S03R S02OM,SO02NR R 1 0 PO(0R 1 6 )OR 1 and C(O)OM, wherein in RX and RWA, one or more carbons are optionally replaced by 0, NR B N+R 1 3 R 1 5, SO, S02, S+R. PR 1 3 P(O)R13,PRR A phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, 9 and carbohydrate, one or more carbons are optionally replaced by 0, NR, N R R 1 0 5, SO, SO2, S R PR P R R 1 0 A, or P(O)R 9 ~.wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, 0000 alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 NR 1 3 R 1 SR 13 S(O)R 1 3 S02R 1 3 S03R 1 3 NR 1 3 OR NR 1 3 NR 1 4 R 1 N02, C02R 1 3 CN, OM, SO2OM, S02NRl R 1 4 C(O)NR 1 3 R 14 C(O)OM, C0R 1 3 P(O)R 1 3 3 R 1 P R 1 R 1 R1 1 (R 3 14 1~R 3 R 14 A7, an N~ 9 11 R 1 2 439 R1 9 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by 0, NR7, N+R7R8, S, SO, S02, S+R7R8, PR7, P+R7R8, phenylene, heterocycle, quatamary heterocycle, quaternary heteroaryl, or aryl, wherein alkane aiyi, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalicyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 NR 1 3 R 1 SR 1 3 S(O)R 13 S02R 1 3 S03R 1 3 NR 1 3 OR 1 NR 1 3 NR 1 4 R 1 N02, C02R 1 3 CN, OM, S020M, S02NR 1 3 R 1 C(O)N-R 1 R 1 C(0)OM, C0R 1 3 P(O)R 1 3 R 1 P+RRR 1 5A-, P(OR' 3 )OR" 4 S+R' 3 R'A, and N+R R 1 1 R 1 A; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, :0;:::cycloalkyl, and heterocycle can be further substituted with one or more substituent 7 77 :groups selected from the group consisting of OR NR R SR S(O)R S02R, 7 778 *S03R C02R CN, oxo, CONR R NeR 7 RR 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary whero rein ,pIR 7 R 8 A, and P(O)(0R 7 )OR8, and weensaid alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, :**:cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR N +R 7 R 8 S, SO, S02, S +R 7 PR 7 P(O)R 7 P +R 7 R 8 or 25 phenylene. 118. A compound of claim 117, wherein R1,R IA, R 2 and R 2 A are independently selected from the group consisting of H and alkyl. 119. A compound of claim 118, wherein R 1 R IA, RI, and R 2 A are /N T independently selected from the group consisting of H and CI-Cl 0 alkyl. 440 I" ft 120. A compound of claim 119, wherein said alkyl is a C 2 -C7 alkyl. 121. A compound of claim 120, wherein R 1 R A R 2 and R 2 A are independently C 2 -C 4 alkyl. 122. A compound of claim 121, wherein R 1 RI A R 2 and R 2A are independently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. 123. A compound of claim 121, wherein R 3 R 3 A, R 4 and R 4 A are independently selected from the group consisting of H and OR 9 124. A compound of claim 123, wherein R 9 is H. 125. A compound of claim 117, wherein R 7 R 7 A, R 8 and R 8A are H. 126. A compound of claim 117, wherein d and e are independently 1 or 2. 2. S127. A compound of claim 126, wherein d and e are both 2. 128. A compound of claim 117, wherein one or more R x and one or more R A are independently selected from the group consisting of alkyl, aryl, *13 13 14 S: 25 cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 1 NR 13 R 14 NR 13 NR1R 1 5 N R 9 R 1 1 R 12 SR 13 SR 1 3 R 14 C02R 1 3 NR 4 C(O)R 3 and NR 4 C(O)R 13 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NR 9 R 10 N+R 9 R 1 1 R 12 A SR 9 S(O)R 9 S02R 9 SO3R 9 oxo, C02R 9 CN, halogen, CONR 9 R 1 0 S02M, SO 2 NR 9 R' 0 PO(OR 6 )OR 17 p+R 9 R 1 1 R 12 S+R 9 RioA- or C(O)OM, and 441 wherein in RX, one or more carbons are optionally replaced by O, NR 1 3 N+R 13 R 14 S, SO, SO2, S+R 13 PR 13 P(O)R 1 3 P R 1 3 R 14 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 N+R 9 R 10 S, SO, S02, S+R 9 PR 9 PR 9 R 1 0 or P(O)R 9 129. A compound of claim 117, wherein one or more R Y and one or more RyA are independently selected from the group consisting of alkyl, polyether, fluoride, chloride, bromide, iodide, NR 13 R 14 NR 14 C(O)R 13 and OR 3 9 wherein alkyl and polyether can be further substituted with SO3R 9 N+R 9 R 1 1 R 12 and quaternary heteroaryl. 130. A compound of claim 117, wherein R 19 is selected from the group 15 consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and polyalkoxy diyl, wherein alkane diyl and polyalkane diyl can optionally have one or more carbon replaced by O, NR7, N+R7R8, S, SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene. 131. A compound of claim 130, wherein R 19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are 9:9: optionally replaced by O, NR 9 N R 9 R 10 S, SO, S02, S R 9 R 1 0 PR 9 p R 9 R 1 0 phenylene, amino acid, peptide, polypeptide, carbohydrate, or polyalkyl. oo. 2 132. A compound of claim 131, wherein R 1 A R 2 and R 2 A are independently selected from the group consisting of H and alkyl. 133. A compound of claim 132, wherein R 3 R 3 A, R 4 and R 4 A are independently selected from the group consisting of H and OR 9 442 134. A compound of claim 133, wherein R 9 is H. 135. A compound of claim 134, wherein R 7 R 7 A, R 8 and R 8 A are each 136. A compound of claim 135, wherein d and e are independently 1 or 137. A compound of claim 136, having the formula: S N- 9O 9 *99 q 9* 9 .9..o 9 9999 0- 11 C PEG 3400 molecular weight polyethylene glycol polymer chain 138. A compound of formula (V) 443 6 RR 2 A( R 7 A ZZ(Rn, A (RX~q wherein: q is an integer from 0 to 4; r is aninteger from 0to 3; d and e are independently integers from 0 to 2; t is an integer from 0 to 4; u uis ainteger from 0to R R2 ,and R2 are independently selected from the group consisting 10 of H, alkyl, alkenyl, alkynyl, halo alkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, .*.dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituent selected from the group consisting of :15 OR 9 NPR R1, NWR9R1VRwA-,9, SR9- DPD 9 D 1 1 S(O)R S02R, S03R C02R CN, halogen, oxo, and CONRR 1 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR, N+R R 0 S, SO, S02, S R A-7 P R R 1 A- or phenylene, wherein R R and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylan-moniumalcyl, and arylalkyl; or 444 R 1 and R 2 taken together with the carbon to which they are attached form C 3 -C 10 cycloalkylidene, or RI A and R 2A taken together with the carbon to which they are attached form C 3 -CIo cycloalkylidene; R 3 R 3 A, R 4 and R 4 A are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR 9 R 10 SR 9 S(O)R 9 SO2R 9 and SO3R, wherein R 9 and R 1 0 are as defined above; or R 3 and R 4 together form =NOR 1 1 =NNR 1 1 R 12 =NR 9 or =CR 11R 12 or R 3 A and R 4A together form =NOR 1 1 =NNR 1 1 R 12 NR 9 or =CR 1 1 R 12 wherein R 1 1 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, 9 heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 15 NR 9 R 10 SR 9 S(O)R 9 S02R 9 S03R 9 C02R 9 CN, halogen, oxo, and CONR 9 R 10 wherein R 9 and R 10 are as defined above, provided that both R and R 4 cannot be OH, NH2, and SH, or SR11 12 R1 and R 1 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; 20 wherein A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; 7 7A 8 8A R7 R, R 8 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx and R A are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 NR 13 R 14 SR 13 S(O)R 13 S(0)2R 13 S03R 13 S R 1 3 R 1 4 NR 13 R 14 NR 1 3 NR 14 R 1 5 NO2, CO2R 13 CN, OM, 445 S02OM, SO2NR 13 R 14 NR 14 C(O)R 1 3 C(O)\R1 3 R 14 NiR14C(O)R13, C(O)OM, C0R 3 'OR 1 8 S(O)nNRI 8 NR 1 3 R 1 NR 1 8 OR 1 N~R R 1 R A, P +R 9 R1 1 R 1 2 aioacid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalicyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR, NTR R 1 N~R R 1 R 1 A, SR 9 S(O)R S02R S03R oxo, C02R CN, halogen, CONR 9 R 1 0 S020M, S02NR R 1 0 PO(OR' )OR P R 9 R 1 1 R 1 A, S+R 9 R' 0 A, or C(O)OM, and wherein R 1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, hetero cycle, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituent selected from the group consisting of OR 9 NR R 1 0 N R R 1 1 R SR S(O)R S02R S03R oxo, C02R CN, halogen, CONR R 1 0 S03R S02OM, SO2NR R 1 0 PO(0R. 1 )OR 1 and C(O)OM, wherein in R' and RA~, one or more carbons are optionally replaced by 0, NR IN R KRA-, 5, SO, S02, S R A, R P(O)R13, R RA phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, 9 and carbohydrate, one or more carbons are optionally replaced by 0, NR~' N+R R 1 0 S, SO, S02, S R PR 9 P R R 1 0 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally a substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloallcyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 NR 1 3 R 1 SR 1 3 S(O)R 1 3 S02R 1 3 S03R 1 3 NR 1 3 OR 1 NR 1 3 N7R 1 R 1 N02, C02R 1 3 CN, OM, S020M, S02NR 1 3 R 1 446 C(O)NRI3 3 R 1 4 C(O)OM, C0R 1 3 P(O)R 1 3 3 R 14 p1R 1 3 R R1 SN-, P(OR 1 3 )OR 1 4 S+R 1 R 4 and N+R 9 R' IR 12 A, R1 9 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by 0, NR7, N+R7R8, S, SO, S02, SH-R7R8, PR7, P+R7R8, phenylene, heterocycle, quatamary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 NR 1 3 R 1 SR 1 3 S(O)R 1 3 S02R 1 3 S03R 1 3 NR 1 3 OR 1 NR 1 3 NR 1 4 R 1 N02, CO2R 1 3 4CN, OM, S020M, S02NRI 3 RI', C(O)NR 13 R 1 4 C(O)OM, CORI 3 P)RRP+R 1 3 R 1 R15A-, P(0R 13 )OR' 4 S+R'R 1 A, and N+R 9 R 1 1 R 2 A-; 9* wherein one or more Ry and RA are independently selected from fr~om the group consisting of W, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, 9 9 9 quatemary heterocycle, OR 9 7, SR-, S(O)R S02R and S03R wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocycle can be substituted with one or more sub stituent groups independently selected from the ~.group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, 13 1314 1 cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3, NR 1 3 R 1 SR 13 S (O)R 13 S02R 13 S03R 13 NR 1 3 0R 1 4 N 1 3 NR 1 4 R 1 5 N02, C02R 1 3 CN, OM, S020M, S02NR 1 3 R 1 C(O)NR 1 3 R 1 C(O)OM, C0R 1 P(O)R 1 3 R 1 +13 14 13) 14, S13 14X 91112 P R R.R15A-, P(OR )OR R NandN R R RA, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR R SR S(O)R S02R, 447 S03R 7 C02R 7 CN, oxo, CONR 7 R 8 N+R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaterary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 P+R 7 R 8 A and P(O)(OR 7 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 NR 7 RA-, S, SO, SO2, S R 7 A-RP, PR 7 P()R 7 R 7 R 8 or phenylene. 139. A compound of claim 138, wherein R R A R 2 and R 2 A are independently selected from the group consisting of H and alkyl. 140. A compound of claim 139, wherein R R A R 2 and R 2 A are independently selected from the group consisting of H and Ci-Clo alkyl. 141. A compound of claim 140, wherein said alkyl is a C 2 -C 7 alkyl. 142. A compound of claim 141, wherein R R A R and R 2 A are independently C 2 -C 4 alkyl. o oo .9 .20 143. A compound of claim 142, wherein R 1 RIA, R 2 and R 2 A are Sindependently selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl. 144. A compound of claim 138, wherein R 3 R 3 A, R 4 and R 4 A are 25 independently selected from the group consisting of H and OR 9 145. A compound of claim 144, wherein R 9 is H. 0. 146. A compound of claim 138, wherein R 7 R 7 A, R 8 and R 8A are H. 147. A compound of claim 138, wherein d and e are independently 1 or 2. 448 148. A compound of claim 147, wherein d and e are both 2. 149. A compound of claim 138, wherein one or more R x and one or more R A are independently selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR 13 NR 13 R 14 NR 13 NR 1 4 R 1 5 NR 9 R 1 1 R 12 A, SR 13 SR 1 3 R 1 4 C02R 13 NR 4 C(O)R 3 and NR 1 4 C(O)R 3 wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can be further substituted with OR 9 NR 9 R 10 N+R 9 R 1 1 R 12 A SR 9 S(O)R 9 S02R 9 S03R 9 oxo, C02R 9 CN, halogen, CONR 9 R 10 SO 2 M, S0 2 NR 9 R 1 0 PO(OR 6 )OR 17 P R 9 R 1 1 R 12 S+R 9 R 0A or C(O)OM, and wherein in Rx, one or more carbons are optionally replaced by O, NR 13 N+R13R14A-, S, SO, SO2, S+R 1 3 PR 13 P(O)R 3 P R 1 3 R 14 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, 9 S. 15 and carbohydrate, one or more carbons are optionally replaced by O, NR NR 9 R 10 S, SO, S2, SR 9 PR 9 R 9 R 1 0 A, or P(O)R 9 C. 150. A compound of claim 138, wherein one or more R y and one or more RyA are independently selected from the group consisting of alkyl, polyether, 20 fluoride, chloride, bromide, iodide, NR 1 3 R1 4 NR 14 C(O)R 13 and OR 1 3 9 wherein alkyl and polyether can be further substituted with SO3R, N R9R 1 R 1 2 A and quaternary heteroaryl. 151. A compound of claim 138, wherein R 9 is selected from the group o consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and polyalkoxy diyl, wherein alkane diyl and polyalkane diyl can optionally have one or more carbon replaced by O, NR7, N+R7R8, S, SO, S02, S+R7R8, PR7, P+R7R8, or phenylene. 449 152. A compound of claim 151, wherein R 1 9 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by O, NR 9 N R 9 R 10 S, SO, SO2, S R 9 R 10 PR 9 P RR 1 0 phenylene, amino acid, peptide, polypeptide, carbohydrate, or polyalkyl. 153. A compound of claim 152, wherein R R A R 2 and R 2 A are independently selected from the group consisting of H and alkyl. 154. A compound of claim 153, wherein R 3 R 3 A, R 4 and R 4 A are independently selected from the group consisting of H and OR 9 155. A compound of claim 154, wherein R 9 is H. 156. A compound of claim 155, wherein R 7 R 7A R, and R are each 9 9 9 99 90 9 *r 9 9 157. A compound of claim 156, wherein d and e are independently 1 or 158. A compound of claim 157, having the formula: 159. A compound of formula EIn (RX)q R R 4 R 6 R 5 R R" Rs R 4 450 wherein: q is an integer from i to 4; n is an integer from 0 to 2; R. 1 is selected from the group consisting Of C 7 20 alkyl, substituted CI- 20 alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, and R 2 is selected from the group consisting of H, alkyl,'alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamnino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR 9 R' 0 N 4 R 9 VRwA, SR 9 S+R 9 R 0 A, P+R 9 R 10 R1A-, S(O)R 9 S0 2 R. 9 S0 3 R 9 C0 2 R', CN, halogen, oxo, and CONR 9 R 1 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, :(polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR', N+R 9 R. 10 A, S, SO, S02, S+R 9 A, PF' 1 A, or phenylene, wherein R9, R10 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or :R1 and R. taken together with the carbon to which they are attached form C3COcycloalicylidene; 25 R 3 and Wi are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR, NRR 1 SR. 9 S(O)R 9 S0 2 R 9 and SQ 3 R 9 wherein R 9 and R 10 are as defined above; or PR3 and R 4 together formn =NOR' 1 =NNIR" R 2 ,=NIR,or =CR 1 R wherein R" and R 12are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyallyl, cycloalkyl, cyanoalkyl, OR 9 NRR' 0 SR 9 S(O)R- 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 wherein R 9 and R1 0 are as defined above, provided that both R3 and R 4 cannot be ATT-T OH, Nil 2 or SH, orI 451 R" and R 12together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R 6are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9, SR9, S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups- independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 NR1 3 R1 4 SR'1 3 S(O)R 1 3 SO 2 R' 3 S0 3 R 1 3 NR 13 OR 1 4 NR1 3 NI 4 R' 5 NO 2 C0 2 R 1 3 CN, GM, S0 2 0M, S0 2 NR' 3 C(O)NR' 3 C(O)OM, COR' 3 P(O)R' 3 R' p+R 13 R 14 R 5 P(OR' 3 )OR 1 4 S t R1 3 R1 4 and N+R 9 R"R1' 2 A-, A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloallcyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 SR 7 S0 2 R', 20S0 3 R 7 C0 2 R 7 CN, oo CONR 7 1NR 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, ~cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, aP(O)R 7 P~R 7 R 8 R 9 and P(O)(0R and wherein said alkyl, alkenyl, alkynyl, polyallcyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by NP? N~R 7 8 AS, SO, S02, S+R PR 7 P(O)R, P+R 7 R 8 A, or phenylene, and R' 3 R' 4 and R' 5 are independently selected from the group consisting of hydrogen, alkyl,, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and a* quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR', N~R 9 R 0 S, S0, SO 2 S+R 9 A, PR 9 P+R 9 R' 0 K, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and ~ST~ R' 4 and R' are optionally substituted with one or more groups selected fromr the group consisting of sulfoalkyl, quaterna~ry heterocycle, 452 quaternary heteroaryl, OR, NqR 9 R 10 N 4 R 9 R 1 'R1 2 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 10 SO 2 OM, S0 2 NR 9 R 10 PO(0R 16 )OR' 7 P+R 9 R'OR"K'A, S+R 9 R' 0 K, and C(O)OM, wherein R 1 6 and R 17 are independently selected from the substituents constituting R 9 and M; or R 14 and R1 5 together with the nitrogen atom to which they are attached, formn a cyclic ring; R 7 and R' are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quatemnary 13 13 1 1313 13 3 14 heteroaryl, OR NR. R' 4 SR 13 S(O)R S(O) 2 R S0 3 R 13 S R' R A, NR1 3 OR 14 NRDTNR1 4 R 15 NO 2 C0 2 R 13 CN, OM, SO 2 OM, S0 2 NR1 3 R1 4 NR1 4 C(O)R 1 3 C(O)NR' 3 R" 4 NR 14 C(O)R'1 3 C(O)OM, C0R 13 OR18, S(O).NRI 8 NR3R 1, N 18 OR 14 N+R9R R NA P R9R 1 R 12 A, amino acid, peptide, polypeptide, and carbohydrate, so:: wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, halo alkyl, polyether, quaternary hetero cycle, and quaternary 20 heteroaryl can be fither substituted with OR 9 NR 9 R 10 N+R 9 R 1 1 R 2 SR9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 2 0M, *SO 2 NR'R PO(OR j'ORi, 1 S+R9R OA, or C(O)Man wherein R 1 8 is selected from the group consisting of acyl, ego***1.uyauuywiayhtroylheeorl adakl *25wheei aclarylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl,an alkyl, 6 quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR, NRR 10 0: N~WR9R R ,SRS(O)R 9 S0 2 R 9 S0 3 R 9 oxo, CO 2 R9, CN, halogen, CONR9R", S0 3 R 9 S0 2 0M, S0 2 NR'R10, PO(OR 1)O ,an C(O)OM, wherein in Rx, one or more carbons are optionally replaced by 0, NR' 3 Tq+R 1 R 4 S,0S, SO 2 S+R PR 13 P(0)R 1 3 P+R 13 R A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, 453 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N+R 9 R 1 0 A, S, SO, S0,, S+R 9 N, PR 9 P+R 9 R' 0 or P(O)R 9 wherein quaternary heterocycle and quatemary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, halo alkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, 13", NR' 3 SR' 3 S(O)R 13 S0 2 R 13 S0 3 R 13 NaO OR NR 1NR1 R' 5 NO 2 C0 2 R 13 CN, OM, S0 2 0M, so 2 NR1 R14 141 13P14 R 1 R 4 R 1 13 14 C(O)NR 3 R 1 C(O)OM, COR P(O)R' 3 pR3RRAP(OR )OR S+R 13R NA, and NR 9 R R 12A, provided that R5 and R 6 cannot be OH1, and both R 5 and R 6 cannot be hydrogen or SH; provided that when R 5 or R 6 is phenyl, only one of R1 or R 2 is H; and provided that when q 1 and Rxis styryl, anilido, or anilinocarbonyl, -onily one ofR 5 or R 6 is alkyl. A0 0 O.L. 160. A compound of formula R n 8 R R R 0 Rqsa ro 1 3o4 n2sa nee rm0t2 R' an 2 aeidpnetyslce Ro thgrucnstigfHak, alkny6 4lyyhlakl lyayarllyakxakxak susitue wniteoermrusiunsslce from th grou cositngo 454 R 9 NR 9 RO, N+RRORwA-, SR', S-+R 9 R 0 P~R 9 R' 0 R 1 S(O)R 9 S0 2 R 9 S0 3 C0 2 R 9 CN, halogen, oxo, and CONIR 9 R' 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR', NWR 9 R' 0 S, SO, SO 2 S+R 9 P+R 9 R' 0 or phenylene, wherein R 9 R 10 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, amrnoniumalkyl, alkylamnmoniumalkyl, and arylalkyl; or R 1 and R 2 taken together with the carbon to which they are attached form C 3 -CIO cycloalkylidene; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR 9 Rl 0 SR 9 S0 2 R 9 and S0 3 R 9 and R 4 is selected from the group consisting Of C 7 20 alkyl, substituted CI- 20 ailkyl, alkenyl, alkynyl, acyloxy, substituted aryl, anthracenyl, heterocycle, OR41 NR 41 R1 0 SR 41 S(O)R 4 S0 2 R 41 and S0 3 R 9 or R 3 and R 4 together form =N0R 42 =NNR 1 R 4 1' =NR 41 i or =CR 1 'lR 4 wherein R 9 and R 10 are as defined above, .:wherein R 1 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR, NR 9 R 10 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 ~*~*:wherein R 41 is selected from the group consisting Of C 7 20 alkyl, substituted C 1 -20 alkyl, substituted aryl, anthracenyl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl, R 42 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R' 0 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 and R 43 is selected from the group consisting Of C 7 2 o alkyl, substituted CI- 2 0 alkyl, substituted aryl, anthracenyl, arylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cyanoalkyl, OR 9 NR 9 R 1 0 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R 10 said carboxyalkyl, carboalkoxyalkyl and cyanoalkyl comprising C 7 20 alkyl, or 455 R" and R 43 together with the nitrogen or carbon atom to which they are attached form a cyclic ring, provided that both R 3 and R 4 cannot be OH, NH 2 or SH; R 5 and R 6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9 SR 9 S(O)R 9 S0 2 R, and S0 3 R, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quatemrnary heteroaryl, halogen, oxo, OR" 3 NR 13 R' 4 SR13, S(O)R13, SO 2 R 3 S0 3 R 13 NR 1 3 0R 4 NR13NR 14 R5, NO 2 C0 2 R 13 CN, OM, SO20M, SO 2 NR 13 R' 4 C(O)NR 3 R 1 4 C(O)OM, COR13, P(O)R 13 R 1 4 13 14 15 13 14 111 12 P+R 3R 4R.A, P(OR )OR 14 S R' 3 R 1 4A, and NR 9 R"R 2A, wherein R" is as defined above, and R' 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 Ro 10 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR'R, wherein R 9 and R' 0 are as defined above, or 20 R" 1 and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent r ~groups selected from the group consisting of OR, NR 7 R 8 SR 7 S(O)R 7 S0 2 R, S0 3 R 7 C0 2 R 7 CN, oxo, CONR 7 R, NR 7 R 8 R 9 A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 PR 7 RR 9 and and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 NR 7 RA-, S, SO, SO 2 SRAR 7 PR 7 P(O)R 7 PR 7 R or phenylene, S and R 3 R14, and R" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, 456 heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, atkenyl, alkynyl, arylakyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR 9 NWR 9 R 1 0 S, SO, S0 2 S+R 9 PR 9 P+R 9 R 10 A- P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R' 3 R" 4 and R 15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR9R 10 ,-N+R 9 R 1 1 2 NA, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO 2 OM, SO 2 NR 9 R' 0 PO(0R 1 6 )OR' 7 P+R 9 R 10 R' S+R 9 R 10 and C(O)OM, wherein R 1 6 and R 17 are independently selected from the substituents constituting R 9 and M; or R 4 and R 15 together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 and R 8 are independently selected from the group consisting of .hydrogen and alkyl; and one or more RX are independently selected from the group consisting of H, 20 alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR", NR R' 4 SR 13 S(O)RI S(O) 2 R' 3 S0 3 R 1 3 S R 13R 1A, OR 3 R~ 4 N 1 NO 2 C0 2 R' 3 CN, GM, S0 2 0M, S0 2 NRR 4 134C 13 14, N14 13 1 1 18 NR~(O)R",C(O)NR RR C(O)R ,C(O)OM, COR" ,OR" NR 'NR 18 0R' 4 >TR 9 R' 1 R 2 A,P+R 9 R' 1 R 1 amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 NR 9 R' 0 N+R 9 R"R 1 2 A, SR9, S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 2 0M, S0 2 WR PO(OR. ')OR 1 7 P+R 9 R"R 1 2 K, S RR'O- orROO n wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, h eterocycle, heteroaryl, and alkyl, ~STA~ wherein acyl, arylalkoxycarbonyl, arylailkyl, heterocycle, heteroaryl, alkyl, (4quaternary hetero cycle, and quaternary heteroaryl. optionally are substituted with 457 one or more substituents selected from the group consisting of OR, NIRR, NWRR'" 1 2 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONRR' 0 S0 3 R 9 S0 2 0M, SONRR', PO(OR 1 6 )OR' 7 and C(O)OM, wherein in RW, one or more carbons are optionally replaced by 0, NR 13 NiR 3 R 1 4 A, S, SO, SO 2 S R 13A, PR 1 3 P(O)R 1, P R 13R 14A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N+R 9 R' 0 K, S, SO, S02, S+R 9 X, PR', P+R 9 R' 0 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR 13 R 1 4 SR 1 3 S(O)R 13 SO 2 R' 3 S0 3 R 3 NR13OR 1,N N RRI R, ,N0 2 CO 2 R" ,CN, OM, S 2 0M, S0 2 NR 13R14 C(O)NR 3 R 14 C(O)OM, C0R 1 3 P(O)R 13 R 1 4 P+R 3 R 14 R 15 P(OR' 3 )OR 1 4 ~*141 12X S+R' 3 R 1 and N+R 9 R R1NR Sprovided that R 5 and R 6 cannot be OH, and both R5 and R 6 cannot be hydrogen or SH;2 6 provided that when R or R 6 is phenyl, only one of R1 or R is H; and 20 provided that when q =1 and RX is styryl, anilido, or anilinocarbonyl, only one of R 5 or R 6 is alkyl. 458 161. A compound of formula SR8 1 2 R 1 (Rx)q~ 3 .I R 3 R 6 R 5 RI4 wherein: q is an integer from I to 4; n is aninteger from 0to 2; R' and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, aiylalkyl, alkoxy, ~10 alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more sub stituents selected from the group consisting of NR 9 N+RRIORWA, SR, SR'A,PRR 0 Rl'A-, S S 0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR', N+R 9 R"AK, S, SO, SO 2 S+R 9 P+R 9 R 10 A- or phenylene, wherein R 9 R10, and Rw are independently selected from the group consisting of H, alkyl, aikenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, atkylammoniumalkyl., and arylalkyl; or R' and R 2 taken together with the carbon to which they are attached form C 3 -CIO cycloalkylidene; R 3 and RW are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NIR 9 R' 0 SR, S(O)R 9 S0 2 R 9 and 50 3 R 9 wherein R 9 and R1 0 are as defined above; or R 3and R 4 together form =NNR"R 1, NRW, or =R R1 wherein R" and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, 459 heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R' 0 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R. 9 CN, halogen, oxo, and CONR 9 RIO) wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 canmot be OH, NH 2 or SN, or R" and R 1 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 is selected from the group consisting Of C 7 20 alkyl, substituted CI- 20 alkyl, alkenyl, alkynyl, substituted aryl, anthracenyl, cycloallcyl, heterocycle comprising at least one phosphorus heteroatom, quaternary heterocycle, OR 51 SR 5 1 S(O)R, SO 2 RS, and SO3R9 wherein said R 5 substituted C 1 -20 alkyl and substituted aryl Substituents independently comprise one or more substituent groups that are selected from the group consisting Of C 7 2 o alkyl, C 7 2 o alkenyl, C 7 2 o alkynyl, polyalkyl, polyether, aryl, haloalcyl, cyclo alkyl, heterocycle, arylalkyl, quaternary heterocycle, quatemnary heteroaryl, oxo, OR 52 N 5 2 R 1 4 SR 52 S(O)R 52 S0 2 R 52 S0 3 R" 3 ia 1 OR NqR'NR 1 4 C0 2 R OM, S0 2 0M, SO 2 NR' 3 C(O)NR 13 R 1 C(O)OM, COR' 3 P(O)R' 3 R P+R' 3 R1 4 R"A- P(OR 13 )OR 1 s+R1 3 R'A, and NRIRIRA, and wherein said R 5 C 7 2 alkyl, alkenyl, alkynyl, anthracenyl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl substituents can be substituted with one or more substituent groups independently selected from the grop cnsitin ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, halogen, oxo, ORR SNS2 0 OR' N R INR 14R 15 NO 2 C0 2 R 1 3 CN, OM, SO 2 O0v, SO 2 NR1 3 R1 4 C(O)NR1 3 R1 4 C(O)oM, COR' 3 P(O)R' 3 R' PRR'A, P(OR 3 OR' S~'R' 4 A, n S S N 4 R 9 R"R and R 6is selected from the group consisting of H, alkyl, alkenyl, alkcynyl, aryl, cycloalcyl, heterocycle, quatemnary heterocycle, OR 9 SR 9 S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein said R 6 alkyl, alkenyl, alkynyl, aryl, cycloalcyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl substituents can be substituted with one or more substituent groups independently selected from the group Cnsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, 460 cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 NR 3 R 14 SR1 3 S(O)R13, SO 2 R' SO 3 R 13, N130RR14 NR 13 NR 14 R' 15 NO 2 CO 2 R13, CN, OM, SO 2 OM, SO 2 NR 1 3 R 1 4 C(O)NR 3 R 14 C(O)OM, COR 13 P(O)R 3 R 14 p+R 13 R' 4 R 15 A, P(OR 13 )R 14 S+R 3 R 4 A, and NR 9 R R 2A-, A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent 0 groups selected from the group consisting of OR 7 NR 7 R 8 SR 7 S(O)R 7 S0 2 R 7 SO 3 R7, C0 2 R 7 CN, oxo, CONR 7 R 8 N R 7 R 8 R 9 A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quatemrnary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 P+R7R R9A-, and P(0)(OR )OR and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 WNR 7 R 8 A, S, SO, S02, S+R 7 PR 7 P(O)R 7 P+R 7 R 8 A, or phenylene, and wherein R 9 is defined as above, 99 9* RS is selected from the group consisting of C 7 2 0 alkyl, substituted C 1 20 0 alkyl, substituted aryl, anthracenyl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl, R52 is selected from the group consisting of C 7 2 0 alkyl, substituted C 1 2 0 alkyl, polyalkyl, substituted aryl, anthracenyl, arylalkyl, heterocycle, heteroaryl, S quatemrnary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, and R 3 R 14 and R 1 S are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quatemrnary heterocycle, quatemary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9 N+R 9 R 1 A S, SO, S02, S'R 9 AK, PR 9 P+R 9 R'OA 1 P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, R's and R 5 2 are optionally substituted with one or more groups se d from the group consisting of sulfoalkyl, quaternary heterocycle, 461 quaternary heteroaryl, OR', NRR, N+R 9 R" 1 2 SR 9 S(O)R 9 SO 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 2 0M, SO 2 NR 9 R' 0 PO(OR' 6 )0R 1 P~kRR R NS+R9R'- an (O)OM, wherein R 1 6 and R1 7 are independently selected from the substituents constituting R 9 and M; or R 1 4 and R1 5 together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more RX are independently selected from the group consisting of H, alkyl, alkenyl., alkynyl, polyalkyl, acyloxy, aryl, arylalkyl., halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quatemnary 13 13 14 13 13 1 heteroaryl, OR NR R SR", S(O)R. S(O) 2 R S0 3 R' 3 S+R 13 R 1 A, NqR3 OR 1, NqRDNRI R" 5 NO 2 CO 2 R CN, OM, SO 2 OM, S0 2 NR 13R 4 NR' 4 C(O)R 13 C(O)NR 13 R 14 NR' 4 C(O)R 13 C(O)OM, COR 1 3 O18, S(O)nNR", iqR139 1811R 4 12 R. 1 12 R 1 R 18 OR 8 R 4 N 4 R9R 'R K, P+ RR RA-, amino acid, pe ptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, 20acyloxy, arylalkyl, haloalkyl, polyether, quatemnary heterocycle, and quaternary heteroaryl. can be further substituted with OR 9 NRR, NR 9 Rl IR 12 SR 9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 10 SO 2 OM, P 1O' 6 )0R 1 7 12 SO 2 NR 9 R',OO O, P+R 9 R. 1 R' A, S+R 9 R 1 N, or C(O)OM, and wherein Ri selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl., heterocycle, heteroaryl, and alkyl, 25 wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quatemnary heteroaryl. optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR 9 R' 0 N+R9R 1R 12A, SR9, S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 3 R 9 S0 2 0M, SO 2 NR 9 Rrn, PO(0R 1 6 and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by 0, NR' 3 N+R 13 R 4 A, S, SO, SO 2 S+R 13 A, PR 13 P(O)R 13 P+R 13 R 4 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, 462 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 WR 9 R 1 0 S, SO, SO,, S+R 9 PR 9 P-'R 9 R' 0 K, or P(O)R'; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 N RD R. 14 SR1', S(O)R 13 SO 2 R' 3 S0 3 R 13 NqR 13 OR 14 NR 13 qR 1 4 R 15 NO 2 C0 2 R 13 CN, OM, SO 2 OM, S0 2 NR 1 'R 14 C(O)NRI R 1, C(O) OM, COR 1 3 P(O)R1 3 R 14 P +R1 3 R1 4 R 5 (0R 13 )OR 1 4 S R 1 R 4 and N 4 'R 9 R"R 12 x, provided that R 6cannot be OH; provided that when R 5 or R 6 is phenyl, only one of R 1 or R 2 is H; and provided that when q I and RX is styryl, anilido, or anilinocarbonyl, only one of R 5 or R 6 is alkyl. 162. A compound of formula 01 R S R 4 R 3. wherein: q is an integer from i to 4; n is an integer from 0to 2; R 1 and RW are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialicylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of 463 ORN9R10N+R1wA-,SR'S+RROA-,P+R 9 RIORIIKS (O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NP?, N+R 9 R 0 S, SO, S02, S+R 9 P+RWR 1 A or phenylene, wherein R 9 R1 0 and RW are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, animoniumalkyl, alkylainmoniumalkyl, and arylalkyl; or R' and R 2 taken together with the carbon to which they are attached form C 3 -CIO cycloalkylidene; R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR 9 R 10 SR', S(OWR, S0 2 R 9 and S0 3 R 9 wherein R 9 and R1 0 are as defined above; or R3 and R 4 together form =NOR" 1 NNIR1 'R 1, =NR9, or =CR1 R12 wherein R 1 1 and R 12 are independently selected from the group consisting a o aof H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R' 0 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R 10 to wherein R 9 and R 10 are as defined above, provided that both R 3 and R4 cannot be OH, NH 2 or SH, or R 1 1 andR 1 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R 6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9, SR9 S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein alkyl, alkenyl., alkynyl, aryl, cycloalkyl, heterocycle, quaternary e heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, 13 arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR NR' 3 SR' 3 S(O)R' 3 S0 2 R' 3 S0 3 R 13 NR1 3 0R 14 RI 3 NR 4 R" 5 NO 2 C0 2 R 1 3 CN, OM, SO 2 OM, S0 2 NR1 3 R 1 4 C(O)NR 3 R 14 C(O)OM, C0R 13 P(O)R1 3 R 14 P+R 13 R 14 R 15 A, P(OR1 3 )OR 14 S+R 13 R 14 A, and N+R 9 R1 R 12A, 464 A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group.consisting of OR 7 NR 7 R 8 SR 7 S(O)R 7 SO 2 R 7 S0 3 R 7 C0 2 R 7 CN, oxo, CONR 7 NR 7 RR 9 A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R, PRRR 9 and P(O)(OR 7 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 NR RR'A, S, SO, SOz2, S R 7 PR 7 P(O)R, PR 7 RA, or phenylene, and R' 3 R 1 4 and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9 NIR 9 R 1 oA-, S, SO, SO2, SS R9A-, PR9, P+R 9 R'OA, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R' 3 R 4 and R' 5 are optionally substituted with one or inore groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, N9R'o, N R 9 R"R 12 A, SR 9 S(O)R 9 SO 2 R 9 SO 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 1 o, S0 2 0M, S0 2 NR 9 Ro, PO(OR16)OR", P+R 9 Ro 0 R 1 1 A, S R 9 R'oA-, and C(O)OM, wherein R 16 and R 17 are independently selected.from the substituents constituting R 9 and M; or R 14 and R together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 is selected from the group consisting of hydrogen and alkyl; R 8 is alkyl; and one or more RX are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR" 3 NR" 3 R' 4 SR", S(0) 2 R 3 S0 3 R 3 S+R' 3 R4A, 465 NR"O 3 0R 4 NR 13 NR' 4 NO 2 CO 2 R' 3 CN, GM, SO 2 OM, SO 2 NP.R R4 NR' 4 C(O)R 13 C(O)NR1 3 R 14 NR 1 4 C(O)R 13 C(O)OM, COR 1 3 OR" 8 S(O),NR' 8 NR1 3 R1 8 NR1 8 0R 1 4 N+R 9 RHR 1' 2 P+R 9 R 1 2 amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, -cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 NR 9 R' 0 N 4 R 9 R' 1 R1 2 SR 9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONRR 0 S0 2 0M, SO 2 NRR, PO(OR")OR, 9R 1A-, S+R0Ao C(O)OM, and wherein R1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NRR 10 N+R 9 R 1 R 1R 2 SR 9 S(O)W 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 10 S0 3 R 9 SO 2 OM, S0 2 NRR 1 0 PO(0R 1 6 )OR' 7 and C(O)OM, wherein in RX, one or more carbons are optionally replaced by 0, NR' 3 N~R N,5,S 2, SRAPR' 3 P(O)R' 3 P+R' 3 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N 4 R 9 R'OA-, S, SO, S02, S+R 9 PR 9 P+R 9 R' 0 A, or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, 25 alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, 13 INR] 3 R 1 SR 13 S(O)R' 3 SO 2 R' SO 3 R' 3 R] 3 0OR 1 4 INRB 3 NRI R 5 N0 2 C0 2 R 1 3 CN, GM, S0 2 0M, SO 2 NR 3 R 1 4 C(O)NRI R 4, C(O)OM, COR" ,P(O)R 13R 1, PR 13R4R15A, P(R 13 )OR 14, S+R 13 R 14 NA, and Nq+R 9 R 1 1 R' 2 x, provided that R 5 and R6 cannot be OH, and both R 5 and R 6 cannot be hydrogen or SH; provided that when R5 or R6 is phenyl, only one of R1 or R 2 is H; and T provided that when q 1 and RX is styryl, anilido, or anilinocarbonyl, only i _s one of R 5 or R 6 -is alkyl. 466 163. A compound of formula S R 1 2 R 1 (RX)q 8 3(I 7 65 4R2 R 3 R 6 R 5 R4 wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R Iand R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, 10 wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of SOR', NR 9 NR1kwxx,K S, S R R S'J2I, S0 3 R 9 C0 2 CN, halogen, oxo, and CONR 9 R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, 1N~R9, NR 9 R 0 S, SO, S02, S+R 9 P t R 9 R 10 K, or phenylene, wherein R 9 R 10 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R 1 and R 2 taken togethe r with the carbon to which they are attached form C 3 -C 10 cycloalkylidene; R 3 and W 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 NR 9 R' 0 SR 9 S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein R 9 and R1 0 are as defined above; or R 3 and R 4 together form =NOR", =NNR 11 R. 12 =NRW, or C R12 467 wherein R" and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R'o, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R, wherein R 9 and R 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or R" and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9 SR 9 S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR' 3 NR' 3 R' 4 SR 3 SO 2 R" 3 SO 3 R' 3 ORR14 13 14R15, NO 2 CO 2 R13 13 14 1314 13 13 14 CN, OM, SO 2 0M, SO 2 NR R 4, C(O)NR1 3 R 4 C(O)OM, COR' 3 P(O)R R4 S* P R' 3 R' 4 R' 5 A7, P(OR13)ORI 4 S+R 3 R1 4 A, and N 4 R 9 R"R1 2 A-, 20 A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR 7 R 8 SR7, S(O)R 7 S0 2 R 7 S0 3 R, C0 2 R, CN, oxo, CONR 7 R 8 NIR 7 RR 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P()R7R, P+RR'R9A and P(O)(OR 7 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 N R 7 RA, S, SO, SO2, SR A, PR 7 P(O)R PR7RA-, or phenylene, andR 3 R 4 and Rs are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quatemrnary heteroaryl, and quaternary heteroarylalkyl, 468 wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR 9 N+R 9 R 10 S, SO, SO,, S+R 9 PR, P+R 9 R"AN, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R 13 R" 4 and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R 10 N+R 9 R 1 1 R'A SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CON7R 9 R' 0 S0 2 0M, S0 2 NR 9 R 10 PO(OR 6 )0R 1 7 P+R 9 R 1 0 R' S+R 9 R' 0 K, and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or R' and R' together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 adR 8 are independently selected from the group consisting of hydrogen and alkyl; and 06::one or more RX substituents are selected from the group consisting Of C 7 20 :alkyl, C 7 20 alkenyl, C 7 20 alkcynyl, substituted C 1 -20 alkyl, substituted C 2 20 alkenyl, substituted C 2 20 alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, haloalkyl comprising 0 9 C 7 20 alkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, 0 20 quaternary heteroaryl, OR6 1 N R R 61, S(O)R 61 S(O) 2 R 61 SOR' 3 S+R' 3 R 4 A NR. 61 OR14 NqRD 3 MR 4 R1 5 C0 2 R 62 OM, SO 2 OM, S0 2 NRI 3 R 1 4 NR' 4 C(O)R 13 C(O)NR 3 R 1 4 N7R' 4 C(O)R'1 3 C(O)OM, C0R 1 3 OR 63 S(O),iNR', 0000TRR3 63 R4 64 R 2 A 12 amn 0 R0 Rn N 64 11R PR' 2 aioacid, peptide, polypeptide, and carbohydrate, 25 wherein R1 8 is selected from the group consisting of acyl, 000: arylalkoxycarbonyl1, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein R 6 1 is selected from the group consisting of C 7 20 alkyl, substituted CI- 20 alkyl, polyalkyl, substituted aryl, anthracenyl, arylalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein R 62 is selected from the group consisting Of C 7 20 alkyl, substituted CI. 20 alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary K heteroarylalkyl, 469 wherein R 63is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, C 7 20 alkyl, and substituted C 1 2 o alkyl, and wherein R 64 is selected from the group consisting Of C 7 2 0 alkyl, substituted C 1 I-20 alkyl, substituted aryl, anthracenyl, acyl, heterocycle, amnmoniumnalkyl, alkylammoniumalkyl, and arylalkyl, and additional Rx substituents can be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, -arylalkyl, halogen, haloalkyl, cycloalkyl., heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR' 3 NR' 3 SR' 3 S(O)R 13 S(O) 2 R 13 S0 3 R' 3 S+R 1 3 R 14 A, NR3 OR 1, NR13NRI NO 2 C0 2 R 1 3 CN, OM, S0 2 0M, S0 2 NR 13R 4, NR' 4 C(O)R 13 C(O)NR 13 R 1 4 RI 4 C(O)R 13 C(O)OM, C0R 13 OR" 8 S(O)nNRI 8 NR 13 R1 8 NR 8 OR 1 4 N 4 R 9 R' 1 R. K2, P R9R 1R K2A, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, a@ acyloxy, arylailkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary 0 12 0i 0heteroaryl can be further substituted with OR 9 NR 9 R 1 N+R 9 R 1 1 R 1 A, SR9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 10 S0 2 0M, S0 2 NR9R'0, PO(0R 1 6 )OR' 7 P+R 9 R 1 R 1 A, S+R 9 R 1 0 N, or C(O)OM, and wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR', NR 9 R', NWR9R R 12A, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R 10 S0 3 R 9 SO 2 OM, S0 2 NR 9 PO(OR"')OR' 7 and C(O)OM, wherein in one or more carbons are optionally replaced by 0, NR' 3 N+R R S, SO, SO 2 S+R 1 3 K, PR 13 P(O)R 13 PR 13R 14A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amnino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N+R 9 R 1 0 K, S, SO, SO 2 S+R 9 AK, PR 9 P+R 9 R' 0 K, or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alcynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, 719,arylalkyl, halogen, oxo, OR 13 NR' 3 R SR" 3 S(O)R 13 S0 2 R 1 3 S0 3 R 13 470 NR1 3 OR 14 NR1 3 NRI 4 NO,, COR 1 3 CN, OM, SO 2 OM, S0 2 NR 13 R 4 C(O)NRI 3 R 14, C(O)OM, COR 1 3 P(O)R1 3 R 1 4 PR 13 R 4 R1 5 P(OR1 3 )OR 1 4 S+R 3 R1 4 and N+R 9 R" R1 2 A-, provided that R 5 and R 6 cannot be OH, and both R 5 and R6 cannot be hydrogen or SH; provided that when R5 or R 6 is phenyl, only one of R' or R 2 is H; and provided that when q 1 and RX is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl. 164. A compound of formula S.f n S R8S 3 .R 6 *Owherein: is 1 or 2; n is2; R' and R 2 are each alkyl; R' is hydroxy; R 4 and R 6 are hydrogen; R 5 hsthe formula (HI) too: 000 (RI)t wherein t is an integer from 0 to one or more Ry are independently selected from the group consisting of S'XOR 13 NR 13 R 4 and SR1 3 471~ R' 3 and R' 4 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quatemrnary heteroarylalkyl; wherein said R 13 and R 14 alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons replaced by O, NR 9 N 4 R9RoA', S, SO, SO2, S R 9 PR9, P+R9ROA, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide; said R13 and R14 polyalkyl, arylalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl groups are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R 10 N R9R"R 2A-, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO20M, SO 2 NR 9 R' 0 PO(OR' 6 )OR 7 P+R 9 R'IOR"A, S R 9 RA-, and :C(O)OM; and 15 said R 13 and R 4 alkyl, alkenyl, alkynyl, aryl, and cycloalkyl groups are substituted with one or more groups selected from the group consisting of sulfoalkyl, quatemrnary heterocycle, quaternary heteroaryl, OR NR 9 R 10 N+R9R"R 2A-, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 Ro 10 SO 2 M, SO 2 NR 9 R' 0 PO(OR 6 )0R 7 P+R 9 R 1 OR 1 SR 9 R 1 OA-, and see* 20 C(O)OM; and R 9 and Ro 10 are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; R" 1 and R' 2 are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalcyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R' 0 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 Ro 10 wherein R 9 and R1o are as defined above; or R" and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and R16 and R7 are independently selected from the substituents constituting R 9 and M, wherein M is a pharmaceutically acceptable cation; and R 7 and R 8 are hydrogen; and 472 t, i, one or more Rx are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino. 165. The compound of claim 164 wherein R' and R 2 are each n-butyl. 166. The compound of claim 165 wherein R y is OR 1 3 and R 13 is as defined in claim 164. 167. The compound of claim 166 wherein one or more Rx are independently selected from methoxy and dimethylamino. 168. The compound of claim 166 wherein Rx is dimethylamino. :i 169. The compound of claim 166 wherein 15 tis 1; R y is para-OR 1 3 and R 13 is as defined in claim 164. 170. The compound of claim 166 wherein 20 tisl; R y is meta-OR 3 and R' 3 is as defined in claim 164. 9* 171. The compound of claim 166 having the 4R,5R configuration. 172. The compound of claim 167 wherein: R 13 is selected from the group consisting of alkyl, arylalkyl, and quaternary heteroarylalkyl; said R 1 arylalkyl and quaternary heteroarylalkyl groups are optionally substituted with one or more groups selected from the group consisting of quaternary heterocyclyl, quaternary heteroaryl, NR 9 R 1 0 and CONR 9 R' 0 said R 1 3 alkyl group is substituted with one or more groups selected from T the group consisting of quaternary heterocyclyl, quaternary heteroaryl, NR 9 R' 1 and SCONR9R 1 and 473 I'. R 9 and R 10 are hydrogen. 173. The compound of claim 172 wherein Rx is dimethylamino. 174. The compound of claim 172 wherein tis 1; R Y is para-OR13; and R' 3 is as defined in claim 172. 175. The compound of claim 172 wherein tis 1; R y is meta-OR1 3 and R 13 is as defined in claim 172. 176. The compound of claim 172 having the 4R,5R configuration. 177. The compound of claim 164 having the structural formula: 178. The compound of claim 164 having the structural formula: 474 179. A compound of claim 164, having the formula: 0 0.* 0* 0 N (C H 2 C H 3 3 180. A compound of claim 164, having the formula: [A] 475 18 1. A compound of claim 164, having the formula: "O N(CH2CH3). *fee o 0 182. A compound of claim 164, having the formula: 0 ~N(CH2CH3) 3 183. A pharmaceutical composition comprising an anti -hyperlipidemic condition effective amount of a compound of any one of claims 1-164, and a pharmnaceutically acceptable carrier. 184. A pharmaceutical composition comprising an anti-atherosclerotic effective amount of a compound of any one of claims 1- 164, and a pharmaceutically acceptable carrier. 476 185. A pharmaceutical composition comprising an anti- hypercholesterolemia effective amount of a compound of any one of claims 1-164, and a pharmaceutically acceptable carrier. 186. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-164, or a composition of claim 183 in unit dosage form. 187. A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-164, or a composition of claim 184 in unit dosage form. S. 15 188. A method for the prophylaxis or treatment ofhypercholesterolemia comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-164, or a composition of claim 185 in unit dosage form. 20 189. The use of a compound of any one of claims 1-164 for the manufacture of a medicament for the prophylaxis or treatment of a hyperlipidemic condition. 190. The use of a compound of any one of claims 1-164 for the manufacture of a medicament for the prophylaxis or treatment of an atherosclerotic condition. 191. The use of a compound of any one of claims 1-164 for the manufacture of a medicament for the prophylaxis or treatment of hypercholesterolemia. DATED this 24th day of May 2000 D. SEARLE CO., Sits Paten t eys, (Bruce Wellington) 47
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1211258A (en) * 1967-02-01 1970-11-04 Boehringer Sohn Ingelheim Amines
AU3373695A (en) * 1994-09-13 1996-03-29 Monsanto Company Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1211258A (en) * 1967-02-01 1970-11-04 Boehringer Sohn Ingelheim Amines
AU3373695A (en) * 1994-09-13 1996-03-29 Monsanto Company Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

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AU2326697A (en) 1997-10-01
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